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Error, confounding and bias


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Error, confounding and bias

  1. 1. ERROR, BIAS & CONFOUNDING Dr. Amandeep Kaur
  2. 2. CONTENTS  Introduction  ERROR Types of error Random error  Type I & Type II error Systematic error Bias Types of bias Confounding  What to look for in observational studies?
  4. 4. ERROR Is considered as the difference between the unknown correct effect measure value and the study’s observed effect measure value. TYPES OF ERROR:  Random error/Non-differential: use of invalid outcome measure that equally misclassifies cases and controls  Systematic error/Differential: use of an invalid measure that misclassifies cases in one direction and misclassifies controls in another
  5. 5. 14 12 10 8 6 4 2 0 RANDOM ERROR 0 5 10 15 20 25 30 35 X Y With random error Without random error Random error doesn’t affect the average, only the variability around the average
  6. 6. 14 12 10 8 6 4 2 0 SYSTEMATIC ERROR With systematic error Without systematic error 0 5 10 15 20 25 30 Systematic error does affect the average, called as bias X Y
  8. 8. What can be wrong in the study? RANDOM ERROR (=CHANCE) Results in low precision of the epidemiological measure  measure is not precise, but true 1. Imprecise measuring 2. Too small groups Decreases with increasing group size & repeating test. Can be quantified by confidence interval SYSTEMATIC ERRORS (= BIAS) Results in low validity(internal & external) of the epidemiological measure  measure is not true 1. Selection bias 2. Information bias 3.Confounding Does not decrease with increasing sample size or
  10. 10. x xxx 80 90 Diastolic Blood Pressure N True BP (cannula ) Observed BP (cuff) xxxxxxx xxxx Chance Bias Adapted from Fletcher, Fletcher & Wagner,
  13. 13. RANDOM ERROR
  14. 14. REDUCING RANDOM ERROR  Reducing the Risk of Type I Errors:  Lower  (p<0.05)  Repeat the study  Reducing the Risk of Type 2 Errors:  Providing adequate sample size, and  Hypothesizing large differences
  15. 15. BIAS DEFINITION:  Any systematic error in the design, conduct or analysis of a study that results in a mistaken estimate of an exposure’s effect on the risk of disease.
  16. 16. DIRECTION OF BIAS  Positive bias – observed effect is higher than the true value (causal effect)  Negative bias – observed effect is lower than the true value (causal effect) A BETTER APPROACH IS:  Bias towards the null – observed value is closer to 1.0 than is the true value (causal effect)*  Bias away from the null – observed value is farther from 1.0 than is the true value (causal effect)* *Note: 1 is the null value for ratio measures (e.g. OR, RR)
  17. 17. CLASSIFICATION ACCORDING TO STAGES OF RESEARCH Bias is a result of an error anywhere in the study  Literature Review  Study Design  Study Execution  Data Collection  Analysis  Interpretation of Results  Publication
  18. 18. SELECTION BIAS  If the way in which cases and controls, or exposed and non-exposed individuals, were selected is such that an apparent association is observed—even if, in reality, exposure and disease are not associated—the apparent association is the result of selection bias. Results from:  Self selection (volunteering)  Nonresponse (refusal)  Loss to follow-up (attrition, migration)  Selective survival  Health care utilization patterns  Systematic errors in detection and diagnosis of health conditions  Choice of an inappropriate comparison group (investigator
  19. 19. SELECTION BIAS SELF-SELECTION BIAS PUBLICITY BIAS: People referring themselves to investigators following publicity about the study. Considered a threat to validity. For example: study of leukemia among troops present at the Smoky Atomic Test in Nevada, 18% of participants contacted the investigators after publicity, and leukemia may have been over-represented in these people(had an axe to grind) HEALTHY WORKER EFFECT: Occurs before subjects are identified into study Relatively healthy people become or remain workers
  20. 20. SELECTION BIAS DIAGNOSTIC BIAS/WORK-UP BIAS: Occurs before the subjects are identified for study Diagnosis may be influenced by physician’s knowledge of exposure For example: A case-control study: for relationship between DVT and OCPs: general practitioners knew about the possible link between the two…. Could lead to over-estimation of the effect of OCPs on DVT HOSPITAL ADMISSION OR BERKSON’S BIAS: Occurs when the combination of exposure and disease under study increases the risk of hospital admission, thus leading to a higher exposure rate among the hospital cases than the
  21. 21. SELECTION BIAS PREVALENCE-INCIDENCE BIAS: When prevalent cases are used to study exposure-disease relationships Related to the phenomena: Once a person is diagnosed with a disease, they may change the habit that contributed to the disease. Prevalent cases represent survivors of the condition being studied and as survivors may be atypical with respect to exposure status they may misrepresent effects. (Selective survival/Neyman’s bias)
  22. 22. SELECTION BIAS EXCLUSION BIAS:  If the exclusion criteria are different for cases and controls or different for the exposed and non-exposed  A case–control hospital-based study: to find association between breast cancer & reserpine….. women who had medical conditions that would lead to the prescribed use of reserpine were excluded from the control group…. Leading to overestimation of the association between breast cancer and reserpine
  23. 23. SELECTION BIAS In CASE-CONTROL STUDIES: Potential Bias: due to poor choice of controls CASES CONTROL SELECTION Colorectal cancer patients admitted to hospital Patients admitted to hospital with arthritis Colorectal cancer patients admitted to hospital Patients admitted to hospital with peptic ulcers In COHORT STUDY: NON-REPRESENTATIV ENESS Controls probably have high degrees of exposure to NSAIDS Controls probably have low degrees of exposure to NSAIDS Differential loss to follow-up….. Differential Attrition SELECTION BIAS Would spuriously reduce the estimate of effect Would spuriously increase the estimate of effect Subjects in follow-up study of multiple sclerosis may differentially drop out due to disease severity
  24. 24. SELECTION BIAS NON-RESPONSE BIAS: In a prevalence study of asthma, chronic bronchitis, and respiratory symptoms, the characteristics of non-responders and the reasons for non-response were studied. Data were obtained by a mailed questionnaire. Non-responders were contacted by telephone and interviewed using the same questionnaire. Found a significantly higher proportion of current smokers and manual labourers among the non-responders than among the responders. Prevalence rates of wheezing, chronic cough, sputum production, attacks of breathlessness, and asthma and use of asthma medications were significantly higher among the non-responders than among the responders. Ronmark et al,
  25. 25. CONTROLLING SELECTION BIAS  Develop an explicit (objective) case definition.  Enroll all cases in a defined time and region.  Strive for high participation rates.  Take precautions to ensure representativeness. AMONG CASES:  Ensure that all medical facilities are thoroughly canvassed.  Develop an effective system for case ascertainment. AMONG CONTROLS:  Compare the prevalence of the exposure with other sources to evaluate credibility.  Attempt to draw controls from a variety of sources.
  26. 26. INFORMATION BIAS  When the means for obtaining information about the subjects in the study are inadequate so that as a result some of the information gathered regarding exposures and/or disease outcome is incorrect, Information bias can occur. Some sources of information bias are:  Subject variation  Observer variation  Deficiency of tools  Technical errors in measurement
  27. 27. INFORMATION BIAS MISCLASSIFICATION BIAS: Due to inaccuracies in methods of data acquisition, the subjects, at times, may be misclassified. For example, In a case-control study, cases may be misclassified as controls, and vice versa, due to the limited sensitivity and specificity of the diagnostic tests or from inadequacy of information derived from medical or other records. Person’s exposure status may be misclassified
  28. 28. INFORMATION BIAS MISCLASSIFICATION BIAS: Two forms:  Differential: If misclassification of exposure (or disease) is related to disease (or exposure) Women who had a baby with a malformation tend to remember more mild infections that occurred during their pregnancies than mothers of normal infants.  Non-differential: If misclassification of exposure (or disease) is unrelated to disease (or exposure) By mistake, some diseased persons are included in control group and some non-diseased persons in case group(misclassified in regard to diagnosis). As a result, a smaller difference in exposure will be found between our cases and our controls than actually exists between
  29. 29. TYPES OF INFORMATION BIAS  Recall bias  Reporting bias  Bias in abstracting records  Bias in interviewing  Bias from surrogate interviews  Surveillance bias
  30. 30. INFORMATION 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 retrospectively  cases 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 history Those 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
  31. 31. INFORMATION BIAS Reporting bias:  Individuals with severe disease tends to have complete records therefore more complete information about exposures and greater association found  Individuals who are aware of being participants of a study behave differently (Hawthorne effect) Wish bias:  Bias introduced by subjects who have developed a disease and who in attempting to answer the question “Why me?” seek to show, often unintentionally, that the disease is not their fault.  May deny certain exposures related to lifestyle (such as smoking or drinking); if contemplating litigation, may overemphasize workplace-related exposures.  Can be considered one type of reporting bias.
  32. 32. INFORMATION BIAS Surveillance bias:  If a population is monitored over a period of time, disease ascertainment may be better in the monitored population than in the general population  Leads to an erroneous estimate of the relative risk or odds ratio Surrogate interviews:  Obtaining information from person other than subject.  E.g., in case of diseases with high case-fatality rate
  33. 33. CONTROLLING INFORMATION BIAS  Blinding  prevents investigators and interviewers from knowing case/control or exposed/non-exposed status of a given participant  Form of survey  mail may impose less “white coat tension” than a phone or face-to-face interview  Questionnaire  use multiple questions that ask same information  acts as a built in double-check  Accuracy  multiple checks in medical records  gathering diagnosis data from multiple sources
  34. 34. PUBLICATION BIAS OR NON-PUBLICATION BIAS  Occurs because of the influence of study results on the chance of publication. Studies with positive results are more likely to be published than studies with negative results.  May result in a preponderance of false-positive results in the literature.  Bias is compounded when published studies are subjected to meta-analysis.
  35. 35. CONFOUNDING “a confusion of effects” Defined as:  a situation in which the measure of effect of exposure on disease is distorted because of the association of the study factor with other factors that influence the outcome. These other factors are called confounders.
  36. 36. CONFOUNDER  In a study of whether factor A is a cause of disease B, a third factor, factor X, is a confounder if the following are true: 1. Factor X is a known risk factor for disease B. 2. Factor X is associated with factor A, but is not a result of factor A.
  38. 38. Cases of Down syndroms by birth order 180 160 140 120 100 80 60 40 20 0 EXAMPLE OF CONFOUNDING 1 2 3 4 5 Birth order Cases per 100 000 live births Cases of Down Syndrome by Birth Order
  39. 39. EXAMPLE OF CONFOUNDING Cases of Down Syndrom by age groups 1000 900 800 700 600 500 400 300 200 100 0 < 20 20-24 25-29 30-34 35-39 40+ Age groups Cases per 100000 live births Cases of Down Syndrome by Age Groups
  40. 40. EXAMPLE OF CONFOUNDING Birth Order Down Syndrome Maternal Age Maternal age is correlated with birth order and a risk factor even if birth order is low
  41. 41. EXAMPLE OF CONFOUNDING Maternal Age Down Syndrome Birth Order Birth order is correlated with maternal age but not a risk factor in younger mothers
  42. 42. Cases per 100000 1000 900 800 700 600 500 400 300 200 100 0 CONFOUNDING 1 2 3 4 5 < 20 25-29 20-24 35-39 30-34 40+ Birth order Age groups Cases of Down syndrom by birth order and mother's age Cases of Down Syndrome by Birth Order and Maternal Age If 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.
  43. 43. CONTROL OF CONFOUNDING  Control at the design stage Randomization: of subjects to study groups to attempt to even out unknown confounders Restriction: of subjects according to potential confounders (i.e. simply don’t include confounder in study) Matching: subjects on potential confounder thus assuring even distribution among study groups
  44. 44. CONTROL OF CONFOUNDING  Control at the analysis stage Conventional approaches  Stratified analyses  Multivariate analyses Newer approaches  Graphical approaches using Directed acyclic graph(DAGs)  Propensity scores  Instrumental variables  Marginal structural models
  45. 45. What to look for in observational studies?  Is the selection bias present? In a cohort study, are participants in the exposed and unexposed groups similar in all important respects except for the exposure? In a case-control study, are cases and controls similar in all important respects except for the disease in question?  Is the information bias present? In a cohort study, is information about outcome obtained in the same way for those exposed and unexposed? In a case-control study, is information about exposure gathered in the same way for cases and controls?
  46. 46. What to look for in observational studies?  Is confounding present? Could the results be accounted for by the presence of a factor – e.g., age, smoking, diet, -- associated with both the exposure and the outcome but not directly involved in the causal pathway?  If the results cannot be explained by these three biases, could they be the result of chance? What are the relative risk or odds ratio and 95%Confidence Interval? Is the difference statistically significant, and, if not, did the study have adequate power to find a clinically important difference?
  47. 47. What to look for in observational studies?  If the results still cannot be explained, then (and only then) might the findings be real and worthy of note?
  48. 48. IDEAL GROUP COMPARISON MODEL Factors affecting the Dependent Variable 140 120 100 80 60 40 20 0 Control Group Experimental Group Effect Independent Variable Confounder(s) - others Confounder: Placebo effect Confounder: Hawthorne effect Natural history
  50. 50. LITERATURE REVIEW  Foreign language exclusion bias  Literature search bias  One-sided reference bias  Rhetoric bias
  51. 51. STUDY DESIGN  - Selection bias  - Sampling frame bias Berkson (admission rate) bias Centripetal bias Diagnostic access bias Diagnostic purity bias Hospital access bias Migrator bias Prevalence-incidence (Neyman / selective survival; attrition) bias  Nonrandom sampling bias Autopsy series bias Detection bias Diagnostic work-up bias Door-to-door solicitation bias Previous opinion bias Referral filter bias Sampling bias Self-selection bias Unmasking bias
  52. 52. STUDY DESIGN  - Non-coverage bias Early-comer bias Illegal immigrant bias Loss to follow-up (attrition) bias Response bias Withdrawal bias  Non-comparability bias Ecological (aggregation) bias Healthy worker effect (HWE) Lead-time bias Length bias Membership bias Mimicry bias Non-simultaneous comparison bias Sample size bias
  53. 53. STUDY EXECUTION  Bogus control bias  Contamination bias  Compliance bias
  54. 54. DATA COLLECTION  - Instrument bias Case definition bias Diagnostic vogue bias Forced choice bias Framing bias Insensitive measure bias Juxtaposed scale bias Laboratory data bias Questionnaire bias Scale format bias Sensitive question bias Stage bias Unacceptability bias Underlying/contributing cause of death bias Voluntary reporting bias  - Data source bias Competing death bias Family history bias Hospital discharge bias Spatial bias  - Observer bias Diagnostic suspicion bias Exposure suspicion bias Expectation bias Interviewer bias Therapeutic personality bias
  55. 55. DATA COLLECTION  - Subject bias Apprehension bias Attention bias (Hawthorne effect) Culture bias End-aversion bias (end-of-scale or central tendency bias) Faking bad bias Faking good bias Family information bias Interview setting bias Obsequiousness bias Positive satisfaction bias Proxy respondent bias  - Recall bias Reporting bias Response fatigue bias Unacceptable disease bias Unacceptable exposure bias Underlying cause (rumination bias) Yes-saying bias  - Data handling bias Data capture error Data entry bias Data merging error Digit preference bias Record linkage bias
  56. 56. ANALYSIS  - Confounding bias Latency bias Multiple exposure bias Nonrandom sampling bias Standard population bias Spectrum bias  - Post hoc analysis bias Data dredging bias Post hoc significance bias Repeated peeks bias  - Analysis strategy bias Distribution assumption bias Enquiry unit bias Estimator bias Missing data handling bias Outlier handling bias Overmatching bias Scale degradation bias
  57. 57. INTERPRETATION OF RESULTS  Assumption bias  Cognitive dissonance bias  Correlation bias  Generalization bias  Magnitude bias  Significance bias  Under-exhaustion bias
  58. 58. PUBLICATION  All's well literature bias  Positive result bias  Hot topic bias
  59. 59. LEAD TIME BIAS  Overestimation of survival duration among screen detected cases when survival is measured from diagnosis.
  60. 60. LENGTH TIME BIAS Overestimation of survival duration among screen-detected cases due to the relative excess of slowly progressing cases. These are disproportionally identified by screening because the probability of detection is directly proportional to the length of time during which they are detectable.
  61. 61. OVER DIAGNOSIS BIAS  Over diagnosis occurs when all of these people with harmless abnormalities are counted as "lives saved" by the screening, rather than as "healthy people needlessly harmed by over diagnosis".  Screening may identify abnormalities that would never cause a problem in a person's lifetime. For example, prostate cancer screening; it has been said that "more men die with prostate cancer than of it".  Issues unnecessary treatment.
  62. 62. Potential Role of Chance in Affecting the Effect: Meaning of Statistical Significance 77 Factors affecting the Dependent Variable 140 120 100 80 60 40 20 0 Control Group Experimental Group Effect Independent Variable Confounder(s) - others Confounder: Placebo effect Confounder: Hawthorne effect Natural history p< p>
  63. 63. Flawed Model Control groFuacpto rrse acffeecivtinegs t hteh Dee pinenddeenpt eVanrdiabelent variable. 120 100 80 60 40 20 0 Control Group Experimental Group Effect Independent Variable Confounder(s) - others Confounder: Placebo effect Confounder: Hawthorne effect Natural history
  64. 64. Flawed Model Unbalanced confounding variables Factors affecting the Dependent Variable S. Wetstone 90 80 70 60 50 40 30 20 10 0 Control Group Experimental Group Effect Independent Variable Confounder(s) - others Confounder: Placebo effect Confounder: Hawthorne effect Natural history