bias confonder pg lecture series
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Bias and confounders need to be removed or control in every epidemiological studyTRANSCRIPT
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
Bias and Confounders
J KishoreMBBS, MD, PGCHFWM, PGDEE, MSc, MNAMS, FIPHA
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
What is Research?
• Research is a quest for knowledge through diligent search or investigation or experimentation aimed at the discovery and interpretation of new knowledge.
• Lets take one example
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
Increased Susceptibility
Ingestion of Cholera vibrio
Cholera
Exposure to contaminated
water
Effect of cholera toxins on bowel
wall cells
Genetic Factors
Poverty
Malnutrition
Crowded housing
Risk factors for cholera Mechanisms for cholera
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
Healthy
PersonAgent
Exposure to contaminated water
Effect of cholera toxins on bowel wall cellsGenetic Factors
Poverty
Malnutrition
Crowded housing
What are the causes of Susceptibility of healthy
What are Mechanisms
Disease Complications
What Complications?Why?
How can be prevented?
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
“An event, condition or characteristic that preceded the disease event and without
which the disease event either would not have occurred at all or would not have
occurred until some later time.”
Rothman, 1998
Necessary, sufficient and component causes
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
Observed association, could it be:
Assessing the Assessing the relationship relationship
between a possible between a possible cause and an cause and an
outcomeoutcome
Selection or measurement bias
Confounding
Chance
Causal
No
No
Probably Not
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
Fact = Truth + Error
(Systematic) (Random)
Bias Chance
Research Method•Type of study•Randomization•Stratification•Blinding
Statistics• p value• confidence interval• Sample size
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
Validity of Research
• It is the degree to which a research /test / survey measures what it is intended to measure.
• It is the ability of research to detect the truth (disease/health event/finding).
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
THREATS TO VALIDITY
A study’s internal validity, or how close its findings are to the TRUTH, can be compromised by three things….
• BIAS• 3rd VARIABLES (CONFOUNDING or
INTERACTION)
• CHANCE
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
Relationship between bias and chance
80 90Diastolic Blood Pressure (mm Hg)
No. of Observations
True BloodPressure (Intraarterial)
Blood Pressure (Sphygmomanometer)
Bias
Non Differential Misclassification
Chance
FaultyInstrument/
Observation
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
Sample Sample
All patients with the conditions of interest
Study on Sampled Patients
Selection
MeasurementConfounding
Chance
CONCLUSIONGeneral Population Having Normal &
Diseased persons
Internal Validity and Generalizability (External Validity)
Internal ValidityExternal Validity
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
External Validity/Generalizability
Internal Validity
Cross Sectional Studies
Case Control Studies
Cohort Studies
Non-Randomized Studies
Randomized Controlled Trial
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
What is bias?
• Prejudice; deviation from truth; the concept of bias is the lack of internal validity or incorrect assessment of the association between an exposure and an effect in the target population. Result of such studies can not be extrapolate to general population. There is no external validity without
internal validity.
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
Types of biases
• There may be more than 100 biases, however, for the understanding they are simply divided in to:
• Selection Bias
• Information Bias
References: J Kishore. A Dictionary of Public Health 2007
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
Systematic Errors
Selection Bias
• Ascertainment Bias is systematic error resulting from failure to identify equally all categories of individuals who are supposed to be represented in a group, e.g., study based on specialty hospital.
• Non-Random Sampling bias, e.g. non-representative sample.
• Healthy worker effect is another selection bias which may take place when employed are compared with unemployed.
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
A faulty assumption that occurs because there are systematic differences
in characteristics between those who are selected for study and those who are not.
Selection Bias
Selection Bias
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
Information Bias
• occurs during data collection. The main types of information bias are:
• 1. Misclassification Bias
• 2. Observer/interviewer Bias
• 3. Recall Bias
• 4. Reporting Bias
• 5. Other information biases: Hawthorne effect, loss to follow up,
MISCLASSIFICATION BIAS
Misclassification Bias: the erroneous classification of an individual, a value, or an attribute into a category other than that to which it should be assigned
• often results from an improper “cutoff point” in disease diagnosis or exposure classification;
• Originated when sensitivity and or specificity of the test is low.
• 2 types of misclassification bias– differential (systematic)– non differential (random)
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
Differential misclassification
• Misclassification is different in groups to be compared
• e.g. recall of exposure in disease patients and control. Disease patients will try to recall the exposure more than control group. This will result in greater association in disease and exposure, i.e., moving away from null hypothesis.
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
Differential Misclassification
"True Situation"CasesControls Total
Exp. 85 40 125Not Exp. 15 60 75Total 100 100 200
85X60/15X40 OR= 8.5
30% unexposed misclassified as exposed in cases, 50% of exposed misclassified as unexposed in controls
Cases ControlsExp. 85 + 5 20Not Exp. 10 60 + 20Total 100 100
90X80/10X20 OR=36.0Bias away from the null (1.0)
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
MISCLASSIFICATION BIAS
• Non-differential Misclassification Bias
rate of misclassification does NOT differ between study groups (Cases and Control)– all study groups and control equally
susceptible to inaccuracy in classification, e.g., faulty instrument applied to all disease and control group
– dilutes the true association– RR or OR shifts towards null (1.0)
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
Non-Differential Misclassification
"True Situation"CasesControls Total
Exp. 85 40 125Not Exp. 15 60 75Total 100 100 200
85X60/15X40 OR= 8.5
50% of exposed misclassified as unexposed
Cases ControlsExp. 43 20Not Exp. 15 + 42 60 + 20Total 100 100
43X80/57X20 OR=3.0
Bias towards the null (1.0)
CONTROLLING FOR MISCLASSIFICATION BIAS
• improving sensitivity and specificity of diagnostic tests– raises or lowers the “cutoff point” for
diagnosis
• increasing the completeness of medical records
• multiple questions that ask same information – acts as a built in double-check
• multiple checks in medical records – gathering diagnosis data from multiple
sources
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
Confounding
Now Lets take one situation
Research QuestionIs down syndrome associated with
birth order?
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
Cases of Down syndroms by birth order
0
20
40
60
80
100
120
140
160
180
1 2 3 4 5
Birth order
Cases per 100 000 live births
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
• Could there be another factor (confounding) responsible for Down syndromes?
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
What is “Confounding”?
• From the Latin confundere, to mix together
• “The distortion of the apparent effect of an exposure (e.g. Birth Order) on risk (e.g. Down Syndrome) brought about by the association with other factor[s] (e.g. age of mother) that can influence the outcome”
• A Dictionary of Epidemiology by John Last, 1995.
28 28
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
Cases of Down Syndrom by age groups
0100200300400500600700800900
1000
< 20 20-24 25-29 30-34 35-39 40+
Age groups
Cases per 100000 live
births
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
What is “Confounding”?, continued...
• Confounding Principles:– Indirect (spurious or weaker than we think)
association (A1) between exposure (E) and disease (D) that depends on A2 [and is weaker than direct association (A3) between confounder and disease]
– Confounder (C) must associate with both E & D
A1
A2 A3
30 30
Birth Order(E)
Down syndrome(D)
Age of mother(C)
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
0100200300400500600700800900
1000
Cases per 100000
1 2 3 4 5
Birth order
Cases of Down syndrom by birth order and mother's age
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
EXPOSURE
(coffee drinking)
DISEASE
(heart disease)
CONFOUNDING VARIABLE
(cigarette smoking)
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
Does night light increase the risk of Myopia?
Nightlight exposure before age 2 yrs
Myopia children
Myopic Parents
Quinn et al 1999
Zadnik et al 2000, Gwiazda et al 2000
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
DiseaseOutcome
Exposure
?Confounder
Common feature of Confounder
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
EXAMPLE:Is maternal smoking a risk factor of perinatal death?Is the association confounded by low birth weight?
Perinatal mortality
Maternal smoking
?Low birth
weight
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
OR RATHER:Is low birth weight the reason why maternal smoking is associated to higher risk of perinatal death?
Perinatal mortality
Maternal smoking
Low birthweight
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
BUT THERE COULD BE AN ADDITIONAL QUESTION:Does maternal smoking cause perinatal death by mechanisms other than low birth weight?
Perinatal mortality
Maternal smoking
Low birthweight
Direct toxic effect?
Block by adjustment
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
Confounding
Criteria for a Confounding Factor ( Rothman and Greenland, 1998):
1.A confounding factor must be a risk factor for the disease.
2.A confounding factor must be associated with the exposure under study in the source population (the population at risk from which the cases are derived). Typically, (for a rare disease) check this condition by looking for an association in the control group.
3.A confounding factor must not be affected by the exposure or the disease. In particular, it cannot be an intermediate step in the causal path between the exposure and the disease.
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
Control of ConfoundingApproaches
1. Design Aspects of a StudyRandomization – used in experimental design to allocate individuals
into experimental groups.Restriction – selecting subjects with equal values for variables
which might be confounders (can use complete restriction or partial restriction known as matching).
2. Analytic MethodsStratification – using homogeneous categories; using Direct, Indirect stratification, Mantel Haenszel tests,
Model Fitting – such as regression models-Linear regression, Logistic Regression, etc.
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
Coping with confounders
Matching (mostly in case control studies)
Selection of cases and controls with matching values of the confounding variable
Pair wise matchinge.g in coffee drinking study as a predictor of MI, each case (a
patient with MI) could be matched with one or more controls that smoked roughly the same amount as the case (10-20 cigarettes/day)
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
Coping with confounders
Matching
Advantages: Can eliminate influence of strong confounders Can increase precision (power) by balancing the number
of cases and controls in each stratum May be sampling convenience making it easier to select
controls
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
Coping with confounders
Matching
Disadvantages Time consuming Requires early decision as to which variables are
predictors and which are confounders Requires matched analysis Creates the danger of over matching( matching on a
factor which is not a founder, thereby reducing power)
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
Comparing control of bias in RCT & NRS
Source of bias RCTs Cohort/other NR studies
Comments
Selection bias Randomi-zation
Control for confounders
Many other study-specific threats
Performance bias
(Exposure)
Double-blinding
Exposure measurement
Misclassifica-tion/ non-comparability
Attrition bias Complete F/U
Complete F/U What amount is critical?
Detection bias
(Outcome)
Masked assessmt
Masked assessment
Misclassifica-tion
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
Hill criteria - used to evaluate possibility of causation;
(from Rothman, Modern Epidemiology, 2nd ed., 1998)
1. Strength of association (magnitude of effect): Measured as relative risk or Odds ratio?
2. Consistency - more an argument against associations due to chance. Has effect been seen by others?
3. Specificity - idea that a cause should lead to a single effect - not tenable.
4. Temporality: Did exposure precede outcomes?5. Biologic gradient (dose-response)6. Biologic plausibility: Is the association make sense?7. Coherence (also biologic)—with natural history of
disease/condition. Is the association consistent with available evidence?
8. Experimental evidence: Has a randomized controlled trials been done?
9. Analogy — parallels exposure-outcome relationship for similar exposure and/or disease. Is an association similar to others?
Dr. J Kishore Professor MAMC, New Delhi; [email protected]
It’s the beginning !We have a
long way to goThanks- Dr. J Kishore