3Bias is one of the three major threats to internal validity: What is Bias?Bias is one of the three major threats to internal validity:BiasConfoundingRandom error / chance
4Systematic error in design or conduct of a study (Szklo et al, 2000) What is Bias?Any trend in the collection, analysis, interpretation, publication or review of data that can lead to conclusions that are systematically different from the truth (Last, 2001)A process at any state of inference tending to produce results that depart systematically from the true values (Fletcher et al, 1988)Systematic error in design or conduct of a study (Szklo et al, 2000)
5Bias is systematic error Errors can be differential (systematic) or non-differential (random)Random error: use of invalid outcome measure that equally misclassifies cases and controlsDifferential error: use of an invalid measures that misclassifies cases in one direction and misclassifies controls in anotherTerm 'bias' should be reserved for differential or systematic error
6Random ErrorPer CentSize of induration (mm)WHO (www)
7Systematic ErrorPer CentSize of induration (mm)WHO (www)
8Chance vs Bias Chance is caused by random error Bias is caused by systematic errorErrors from chance will cancel each other out in the long run (large sample size)Errors from bias will not cancel each other out whatever the sample sizeChance leads to imprecise resultsBias leads to inaccurate results
9Types of Bias Selection bias Information (misclassification) bias Unrepresentative nature of sampleInformation (misclassification) biasErrors in measurement of exposure of diseaseConfounding biasDistortion of exposure - disease relation by some other factorTypes of bias not mutually exclusive(effect modification is not bias)This classification is by Miettinen OS in 1970sSee for example Miettinen & Cook, 1981 (www)
10Selection BiasSelective differences between comparison groups that impacts on relationship between exposure and outcomeUsually results from comparative groups not coming from the same study base and not being representative of the populations they come from
16Selection Bias Examples Case-control study:Controls have less potential for exposure than casesOutcome = brain tumour; exposure = overhead high voltage power linesCases chosen from province wide cancer registryControls chosen from rural areasSystematic differences between cases and controls
18Selection Bias Examples Cohort study:Differential loss to follow-upEspecially problematic in cohort studiesSubjects in follow-up study of multiple sclerosis may differentially drop out due to disease severityDifferential attrition selection bias
19Selection Bias Examples Self-selection bias:- You want to determine the prevalence of HIV infection- You ask for volunteers for testing- You find no HIV- Is it correct to conclude that there is no HIV in this location?
20Selection Bias Examples Healthy worker effect:Another form of self-selection bias“self-screening” process – people who are unhealthy “screen” themselves out of active worker populationExample:- Course of recovery from low back injuries in year olds- Data captured on worker’s compensation records- But prior to identifying subjects for study, self-selection has already taken place
21Selection Bias Examples Diagnostic or workup bias:Also occurs before subjects are identified for studyDiagnoses (case selection) may be influenced by physician’s knowledge of exposureExample:- Case control study – outcome is pulmonary disease, exposure is smoking- Radiologist aware of patient’s smoking status when reading x-ray – may look more carefully for abnormalities on x-ray and differentially select casesLegitimate for clinical decisions, inconvenient for research
22Types of Bias Selection bias Unrepresentative nature of sample** Information (misclassification) bias **Errors in measurement of exposure of diseaseConfounding biasDistortion of exposure - disease relation by some other factorTypes of bias not mutually exclusive(effect modification is not bias)
23Information / Measurement / Misclassification Bias Method of gathering information is inappropriate and yields systematic errors in measurement of exposures or outcomesIf misclassification of exposure (or disease) is unrelated to disease (or exposure) then the misclassification is non-differentialIf misclassification of exposure (or disease) is related to disease (or exposure) then the misclassification is differentialDistorts the true strength of association
24Information / Measurement / Misclassification Bias Sources of information bias:Subject variationObserver variationDeficiency of toolsTechnical errors in measurement
25Information / Measurement / Misclassification Bias Recall bias:Those exposed have a greater sensitivity for recalling exposure (reduced specificity)- specifically important in case-control studies- when exposure history is obtained retrospectivelycases may more closely scrutinize their past history looking for ways to explain their illness- controls, not feeling a burden of disease, may less closely examine their past historyThose who develop a cold are more likely to identify the exposure than those who do not – differential misclassification- Case: Yes, I was sneezed on- Control: No, can’t remember any sneezing
26Information / Measurement / Misclassification Bias Reporting bias:Individuals with severe disease tends to have complete records therefore more complete information about exposures and greater association foundIndividuals who are aware of being participants of a study behave differently (Hawthorne effect)
27Controlling for Information Bias - Blindingprevents investigators and interviewers from knowing case/control or exposed/non-exposed status of a given participant- Form of surveymail may impose less “white coat tension” than a phone or face-to-face interview- Questionnaireuse multiple questions that ask same informationacts as a built in double-check- Accuracymultiple checks in medical recordsgathering diagnosis data from multiple sources
28Types of Bias Selection bias Information (misclassification) bias Unrepresentative nature of sampleInformation (misclassification) biasErrors in measurement of exposure of disease** Confounding bias **Distortion of exposure - disease relation by some other factorTypes of bias not mutually exclusive(effect modification is not bias)
30Cases of Down Syndrome by Birth Order EPIET (www)
31Cases of Down Syndrome by Age Groups EPIET (www)
32Cases of Down Syndrome by Birth Order and Maternal AgeEPIET (www)
33ConfoundingA third factor which is related to both exposure and outcome, and which accounts for some/all of the observed relationship between the twoConfounder not a result of the exposuree.g., association between child’s birth rank (exposure) and Down syndrome (outcome); mother’s age a confounder?e.g., association between mother’s age (exposure) and Down syndrome (outcome); birth rank a confounder?
34Confounding Exposure Outcome Third variable To be a confounding factor, two conditions must be met:ExposureOutcomeThird variableBe associated with exposure- without being the consequence of exposureBe associated with outcome- independently of exposure (not an intermediary)
35Confounding Birth Order Down Syndrome Maternal Age Maternal age is correlated with birth order and a risk factor even if birth order is low
36Confounding ? Maternal Age Down Syndrome Birth Order Birth order is correlated with maternal age but not a risk factor in younger mothers
37Confounding Coffee CHD Smoking Smoking is correlated with coffee drinking and a risk factor even for those who do not drink coffee
38Confounding ? Smoking CHD Coffee Coffee drinking may be correlated with smoking but is not a risk factor in non-smokers
39Confounding Alcohol Lung Cancer Smoking Smoking is correlated with alcohol consumption and a risk factor even for those who do not drink alcohol
40Not related to the outcome Not an independent risk factor Confounding ?SmokingCHDYellow fingersNot related to the outcomeNot an independent risk factor
41Confounding ?DietCHDCholesterolOn the causal pathway
42ConfoundingImagine you have repeated a positive finding of birth order association in Down syndrome or association of coffee drinking with CHD in another sample. Would you be able to replicate it? If not why?Imagine you have included only non-smokers in a study and examined association of alcohol with lung cancer. Would you find an association?Imagine you have stratified your dataset for smoking status in the alcohol - lung cancer association study. Would the odds ratios differ in the two strata?Imagine you have tried to adjust your alcohol association for smoking status (in a statistical model). Would you see an association?
43ConfoundingImagine you have repeated a positive finding of birth order association in Down syndrome or association of coffee drinking with CHD in another sample. Would you be able to replicate it? If not why?You would not necessarily be able to replicate the original finding because it was a spurious association due to confounding.In another sample where all mothers are below 30 yr, there would be no association with birth order.In another sample in which there are few smokers, the coffee association with CHD would not be replicated.
44ConfoundingImagine you have included only non-smokers in a study and examined association of alcohol with lung cancer. Would you find an association?No because the first study was confounded. The association with alcohol was actually due to smoking. By restricting the study to non-smokers, we have found the truth. Restriction is one way of preventing confounding at the time of study design.
45ConfoundingImagine you have stratified your dataset for smoking status in the alcohol - lung cancer association study. Would the odds ratios differ in the two strata?The alcohol association would yield the similar odds ratio in both strata and would be close to unity. In confounding, the stratum-specific odds ratios should be similar and different from the crude odds ratio by at least 15%. Stratification is one way of identifying confounding at the time of analysis.If the stratum-specific odds ratios are different, then this is not confounding but effect modification.
46ConfoundingImagine you have tried to adjust your alcohol association for smoking status (in a statistical model). Would you see an association?If the smoking is included in the statistical model, the alcohol association would lose its statistical significance. Adjustment by multivariable modelling is another method to identify confounders at the time of data analysis.
47ConfoundingFor confounding to occur, the confounders should be differentially represented in the comparison groups.Randomisation is an attempt to evenly distribute potential (unknown) confounders in study groups. It does not guarantee control of confounding.Matching is another way of achieving the same. It ensures equal representation of subjects with known confounders in study groups. It has to be coupled with matched analysis.Restriction for potential confounders in design also prevents confounding but causes loss of statistical power (instead stratified analysis may be tried).
48ConfoundingRandomisation, matching and restriction can be tried at the time of designing a study to reduce the risk of confounding.At the time of analysis:Stratification and multivariable (adjusted) analysis can achieve the same.It is preferable to try something at the time of designing the study.
49Effect of randomisation on outcome of trials in acute pain Bandolier Bias Guide (www)
50Confounding Obesity Mastitis Age In cows, older ones are heavier and older age increases the risk for mastitis. This association may appear as an obesity association
51ConfoundingIf each case is matched with a same-age control, there will be no association (OR for old age = 2.6, P = )(www)
53Cases of Down Syndrome by Birth Order and Maternal AgeIf each case is matched with a same-age control, there will be no association. If analysis is repeated after stratification by age, there will be no association with birth order.EPIET (www)
55Confounding or Effect Modification Birth WeightLeukaemiaSexCan sex be responsible for the birth weight association in leukaemia?- Is it correlated with birth weight?- Is it correlated with leukaemia independently of birth weight?- Is it on the causal pathway?- Can it be associated with leukaemia even if birth weight is low?- Is sex distribution uneven in comparison groups?
56Confounding or Effect Modification Birth WeightLeukaemiaSexOR = 1.5Does birth weight association differ in strength according to sex?Birth WeightLeukaemiaBOYSOR = 1.8GIRLSBirth Weight/ /LeukaemiaOR = 0.9
57Effect modification is similar to interaction in statistics. In an association study, if the strength of the association varies over different categories of a third variable, this is called effect modification. The third variable is changing the effect of the exposure.The effect modifier may be sex, age, an environmental exposure or a genetic effect.Effect modification is similar to interaction in statistics.There is no adjustment for effect modification. Once it is detected, stratified analysis can be used to obtain stratum-specific odds ratios.
58Effect modifier Confounding factor Belongs to nature Belongs to study Different effects in different strataSimpleUsefulIncreases knowledge of biological mechanismAllows targeting of public health actionConfounding factorBelongs to studyAdjusted OR/RR different from crude OR/RRDistortion of effectCreates confusion in dataPrevent (design)Control (analysis)
60Fallacies HISTORICAL FALLACY ECOLOGICAL FALLACY (Cross-Level Bias) BERKSON'S FALLACY(Selection Bias in Hospital-Based CC Studies)HAWTHORNE EFFECT(Participant Bias)REGRESSION TO THE MEAN (Davis, 1976)(Information Bias)
61HOW TO CONTROL FOR CONFOUNDERS? IN STUDY DESIGN…RESTRICTION of subjects according to potential confounders (i.e. simply don’t include confounder in study)RANDOM ALLOCATION of subjects to study groups to attempt to even out unknown confoundersMATCHING subjects on potential confounder thus assuring even distribution among study groups
62HOW TO CONTROL FOR CONFOUNDERS? IN DATA ANALYSIS…STRATIFIED ANALYSIS using the Mantel Haenszel method to adjust for confoundersIMPLEMENT A MATCHED-DESIGN after you have collected data (frequency or group)RESTRICTION is still possible at the analysis stage but it means throwing away dataMODEL FITTING using regression techniques
63Effect of blinding on outcome of trials of acupuncture for chronic back pain Bandolier Bias Guide (www)
64WILL ROGERS' PHENOMENON Assume that you are tabulating survival for patients with a certain type of tumour. You separately track survival of patients whose cancer has metastasized and survival of patients whose cancer remains localized. As you would expect, average survival is longer for the patients without metastases. Now a fancier scanner becomes available, making it possible to detect metastases earlier. What happens to the survival of patients in the two groups? The group of patients without metastases is now smaller. The patients who are removed from the group are those with small metastases that could not have been detected without the new technology. These patients tend to die sooner than the patients without detectable metastases. By taking away these patients, the average survival of the patients remaining in the "no metastases" group will improve. What about the other group? The group of patients with metastases is now larger. The additional patients, however, are those with small metastases. These patients tend to live longer than patients with larger metastases. Thus the average survival of all patients in the "with-metastases" group will improve. Changing the diagnostic method paradoxically increased the average survival of both groups! This paradox is called the Will Rogers' phenomenon after a quote from the humorist Will Rogers ("When the Okies left California and went to Oklahoma, they raised the average intelligence in both states").(www)See also Festenstein, 1985 (www)