Pharmacoepidemiology Study design Information bias & selection bias Rob Heerdink
Dr Rob Heerdink Pharmacoepidemiology & Pharmacotherapy Utrecht Institute for Pharmaceutical Sciences Universiteit Utrecht ...
 
Drug development discovery Discovery & screening Proof of Concept first administration to man registration & launch approx...
Relevant questions in practice following registration <ul><li>effect on hard endpoints </li></ul><ul><li>long term (side)e...
DOMAIN Determinant(s) Endpoint(s) time <ul><ul><li>yes / no comparison </li></ul></ul><ul><ul><li>experimental or observat...
Research designs <ul><li>Follow-up (cohort) </li></ul><ul><li>Prospective </li></ul><ul><li>Experimental (clinical trial) ...
Hierarchy of designs <ul><li>1. Meta-analysis of clinical trials </li></ul><ul><li>2. Clinical trial </li></ul><ul><li>3. ...
Study design Past   Present    Future Retrospective Cohort Prospective Cohort Case-Control (retrospective) Cross-sectional
<ul><li>Clinical trials </li></ul><ul><ul><li>Randomisation </li></ul></ul><ul><ul><ul><li>Aim is to create groups with si...
Source population Randomisation Index group Control group Follow-up Follow-up Outcome Outcome In- and exclusion criteria M...
Pharmacoepidemiological designs <ul><li>Descriptive methods  (Signal detection, hypothesis generating).  I dentifying prev...
Evaluation of therapy: golden standard Randomised Controlled Clinical Trial (RCT) Randomise: why?  Controlgroup: why? Blin...
Experiments are often impossible Ethical (e.g. smoking, birth defects) Practical (e.g. rare adverse effects) Non-experimen...
Do animals bite more during a full moon? Bhattacharjee C et al. BMJ 2000;321:1559-61
Observational studies Past   Present    Future Retrospective Cohort Prospective Cohort Case-Control (retrospective) Cross-...
<ul><li>Case Report / Case series </li></ul><ul><li>Describes characteristic association in one / some </li></ul><ul><li>p...
The Lancet, 1961
LETTER TO THE EDITOR THALIDOMIDE AND CONGENITAL ABNORMALITIES Sir, Congenital disorders are present in  approximately 1.5%...
Dwarsdoorsnede onderzoek  beschrijft een karakteristieke relatie tussen determinant en uitkomst op 1 moment in de tijd Cau...
 
Voorbeeld  dwardoorsnede onderzoek Polymorphisms of the LEP- and LEPR gene and obesity in patients using antipsychotic med...
Voorbeeld :  LEPR onderzoek Populatie: 200 antipsychotica gebruikers Determinanten:  LEPR  Q223R en  LEP  promoter 2548G/A...
** p<0.05 Voorbeeld :  LEPR onderzoek N BMI>30 Males QQ 30 6 (20%) QR 73 16 (21%) RR 31 8 (26%) Females QQ 17 12 (71%) ** ...
Observational Cohort <ul><li>Group of individuals with common inclusion criteria is followed over time until an endpoint o...
Cohort study / Follow-up study Study population Exposed Non-exposed Disease + Disease + Disease - Disease -
Voorbeeld cohort onderzoek <ul><li>Zijn patiënten die van specialité naar generiek antihypertensivum switchen minder thera...
Switchers: 13,6% therapie-ontrouw Niet switchers: 18,7% therapie-ontrouw  Van Wijk et al 2006
A cohort study <ul><li>RR (myocardial infarction)* </li></ul><ul><li>Untreated normotensive and hypertensive men 1.0 (refe...
Another cohort study <ul><li>RR (stroke) </li></ul><ul><li>Untreated “Candidates”* for treatment 1.0 (reference) </li></ul...
Frequency measures cohort study (P1 personyears) (P0 personyears) A1 A0 Exposure No Exposure Disease Disease No disease Ti...
Frequency measures <ul><li>Incidence </li></ul><ul><ul><li>Cumulative incidence (CI) </li></ul></ul><ul><ul><li>Incidence ...
Risk disease + | exposure + = A1 / N1 = CI 1   Risk disease + | exposure -  = A0 / N0 = CI 0 Frequency measures cohort stu...
Force of morbidity | exposure + = A1 / P1 = IC 1   Force of morbidity | exposure - = A0 / P0 = IC 0 Frequency measures coh...
Effect measures cohort study
Pill and Deep Venous Thrombosis <ul><li>Risk no pill  = 3.9 per 100 000 py </li></ul><ul><li>Risk pill gen. 2 = 10.3 per 1...
Analysis cohort study <ul><li>Survival analysis </li></ul><ul><ul><li>Kaplan Meier (CI) </li></ul></ul><ul><ul><li>Cox reg...
Kaplan Meier
Prospective vs. retrospective Cohort Studies <ul><li>Prospective Cohort Studies </li></ul><ul><ul><li>Time consuming, expe...
Selection of the Exposed Population <ul><li>Sample of  the general population: </li></ul><ul><ul><li>Geographically area, ...
Selection of the Comparison Population <ul><li>Internal Control Group </li></ul><ul><ul><li>Exposed and non-exposed in the...
Follow up study versus RCT <ul><li>Similarities </li></ul><ul><ul><li>Use of same measures of frequency and association (R...
Cohort study / Follow-up study Study population Exposed Non-exposed Disease + Disease + Disease - Disease -
Case-control study Study Population Cases Controls Exposed Non-exposed Exposed Non-exposed
Example case-control study <ul><li>What is the risk on breast cancer with the use of SSRI antidepressants? </li></ul><ul><...
Coogan et al. Am J Epidemiol 2005
Meaning of odds and odds ratio ? <ul><li>Term from English gambling “4 to 1” </li></ul><ul><li>Odds means chance of succes...
Case Control Exposure + a b - c d a+c b+d Exposure odds among cases = a/c Exposure odds among controls = b/d Exposure Odds...
Rofecoxib and risk of MI <ul><li>Nested Case Control design: </li></ul><ul><li>9218 MI cases of whom 93 used of rofecoxib ...
Selection of cases <ul><li>Establish strict diagnostic criteria for the outcome:  </li></ul><ul><ul><li>Examples: </li></u...
Selection of cases <ul><li>Population-based cases: include all subjects or a random sample of all subjects with the diseas...
Selection of Controls <ul><li>Principles of Control Selection: </li></ul><ul><li>Study base: </li></ul><ul><ul><li>Control...
Selection of Controls <ul><li>General population controls: </li></ul><ul><ul><li>registries, households, telephone samplin...
Ascertainment of outcome and exposure status <ul><li>External sources: </li></ul><ul><ul><li>Death certificates, disease r...
Data Collection External Data Sources Internal Data Sources Exposure Hospital records, employers Questionnaires, physical ...
Strengths in Cohort vs. Case-control? <ul><li>Cohort study </li></ul><ul><li>Rare exposure </li></ul><ul><li>Examine multi...
Limitations in Cohort vs. Case-control? <ul><li>Cohort study </li></ul><ul><li>Not rare diseases </li></ul><ul><li>Prospec...
Validiteit + Precisie -
Validiteit - Precisie +
Validiteit + Precisie +
Validiteit - Precisie -
Precisie en validiteit  (vertekende resultaten)   <ul><li>Toevallige fouten:  </li></ul><ul><li>‘ random error’  (precisie...
Power and precision
Sample size in case-control  study of OC use and MI among women <ul><li>Assuming proportion of current OC use of 10%; </li...
Sample size requirement in RCT <ul><li>baseline risk  number required  </li></ul><ul><li>side effect  in each group </li><...
The likelihood of observing an adverse drug reaction in 2,000 patients Threshold for ADR Probability 1 / 500 0.98 (Lymphom...
Validiteit van onderzoek <ul><li>Komen de bevindingen uit het onderzoek overeen met de werkelijkheid? </li></ul><ul><li>Ex...
Soorten van selectie- en informatiebias <ul><li>Channeling bias </li></ul><ul><li>Referal  bias </li></ul><ul><li>Diagnost...
Information bias (follow-up) <ul><li>Question: do patients who are treated for Hodgkin’s disease have a higher chance of a...
Selecti on  bias  (cohort) <ul><li>Observation a l cohort stud y </li></ul><ul><li>RR (myocardial infarction)* </li></ul><...
Selecti on  bias  (cohort) <ul><li>Observation a l   cohort stud y in the Netherlands </li></ul><ul><li>RR (stroke) </li><...
Case control Time Time Exposure No exposure Exposure No exposure Case (disease) Control (no disease)
Selection of controls <ul><li>Smoking and leukemia </li></ul><ul><ul><ul><li>cases: patients with leukemia </li></ul></ul>...
Information bias (case-control) <ul><li>Drugs and congenital malformation </li></ul><ul><li>Cases  : children with congeni...
Selection bias (case-control) I <ul><li>Oral contraceptives and DVT </li></ul><ul><li>It was published (prospective follow...
Selection bias (case-control) II <ul><li>Women with pain in leg </li></ul><ul><ul><li>Physician asks about use of the pil ...
Methoden om voor vertekende  resulaten te corrigeren <ul><li>Restrictie / Stratificatie </li></ul><ul><li>Mantel Haenszel ...
Risk assessment
 
 
 
Registration of a drug is only the beginning of safety research email: e.r.heerdink@uu.nl twitter: @robheerdink www.slides...
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Farmacoepi Course Leiden 0210 Part 2

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  • Farmacoepi Course Leiden 0210 Part 2

    1. 1. Pharmacoepidemiology Study design Information bias & selection bias Rob Heerdink
    2. 2. Dr Rob Heerdink Pharmacoepidemiology & Pharmacotherapy Utrecht Institute for Pharmaceutical Sciences Universiteit Utrecht The Netherlands www.pharm.uu.nl/epithera
    3. 4. Drug development discovery Discovery & screening Proof of Concept first administration to man registration & launch approx. 10-12 years 10,000 Pre-clinical development 15-30 Fase I/IIa 10-15 Fase IIb/III 1 5 preclinical clinical (I-III) phase IV
    4. 5. Relevant questions in practice following registration <ul><li>effect on hard endpoints </li></ul><ul><li>long term (side)effects </li></ul><ul><li>value compared to other drugs </li></ul><ul><li>effect in populations that were not studied </li></ul><ul><ul><li>children </li></ul></ul><ul><ul><li>elderly </li></ul></ul><ul><ul><li>pregnant </li></ul></ul><ul><ul><li>multiple pathology / drug use </li></ul></ul><ul><li>who benefits and who does not </li></ul><ul><li>less frequently seen adverse effects </li></ul>
    5. 6. DOMAIN Determinant(s) Endpoint(s) time <ul><ul><li>yes / no comparison </li></ul></ul><ul><ul><li>experimental or observational </li></ul></ul><ul><ul><li>retrospective or prospective </li></ul></ul>Study design
    6. 7. Research designs <ul><li>Follow-up (cohort) </li></ul><ul><li>Prospective </li></ul><ul><li>Experimental (clinical trial) </li></ul><ul><li>Observational </li></ul><ul><li>Retrospective </li></ul><ul><li>Case control </li></ul><ul><li>Case series </li></ul>
    7. 8. Hierarchy of designs <ul><li>1. Meta-analysis of clinical trials </li></ul><ul><li>2. Clinical trial </li></ul><ul><li>3. Prospective follow-up (observational) </li></ul><ul><li>4. Retrospective follow-up </li></ul><ul><li>5. Case control </li></ul><ul><li>6. Case series </li></ul>
    8. 9. Study design Past Present Future Retrospective Cohort Prospective Cohort Case-Control (retrospective) Cross-sectional
    9. 10. <ul><li>Clinical trials </li></ul><ul><ul><li>Randomisation </li></ul></ul><ul><ul><ul><li>Aim is to create groups with similar prognosis </li></ul></ul></ul><ul><ul><li>Control group: comparison with placebo or active treatment </li></ul></ul><ul><ul><ul><li>Aim is to evaluate the pharmacological effect of the new compound (exclusion of placebo effect, natural course, measurement error) </li></ul></ul></ul><ul><ul><li>Blinded (single, double, triple) </li></ul></ul><ul><ul><ul><li>Aim is to prevent subjectivity (in patients, researcher, statistician) in the scoring of the prognostic factors and outcome and to prevent differential changes in behaviour (changes that might change prognosis) of the groups to be compared. </li></ul></ul></ul>
    10. 11. Source population Randomisation Index group Control group Follow-up Follow-up Outcome Outcome In- and exclusion criteria Method, blinding Prognostically comparable Treatment Double blind Loss-to-follow-up Blinded measurement of outcome
    11. 12. Pharmacoepidemiological designs <ul><li>Descriptive methods (Signal detection, hypothesis generating). I dentifying previously unrecognised safety issues </li></ul><ul><ul><li>Case reports, </li></ul></ul><ul><ul><li>Case series, </li></ul></ul><ul><ul><li>Cross-sectional study </li></ul></ul><ul><li>Analytical methods (quantifying + risk factors, hypothesis testing). I nvestigating possible hazards (hypothesis-testing in order to substantiate a causal association) </li></ul><ul><ul><li>Observational </li></ul></ul><ul><ul><ul><li>Cohort studies, </li></ul></ul></ul><ul><ul><ul><li>Case-control studies, </li></ul></ul></ul><ul><ul><ul><li>Case-crossover studies </li></ul></ul></ul><ul><ul><li>Intervention </li></ul></ul><ul><ul><ul><li>Experimental Clinical trial </li></ul></ul></ul>
    12. 13. Evaluation of therapy: golden standard Randomised Controlled Clinical Trial (RCT) Randomise: why? Controlgroup: why? Blinding: why? Goal: Only difference between treated and untreated group is the treatment
    13. 14. Experiments are often impossible Ethical (e.g. smoking, birth defects) Practical (e.g. rare adverse effects) Non-experimental (observational) research For example: Do animals bite more often during full moon?
    14. 15. Do animals bite more during a full moon? Bhattacharjee C et al. BMJ 2000;321:1559-61
    15. 16. Observational studies Past Present Future Retrospective Cohort Prospective Cohort Case-Control (retrospective) Cross-sectional
    16. 17. <ul><li>Case Report / Case series </li></ul><ul><li>Describes characteristic association in one / some </li></ul><ul><li>patient(s) between determinant en outcome </li></ul><ul><li>examples: </li></ul><ul><li>serious liverdamage following use of XTC </li></ul><ul><li>birth defects after use of Thalidomide (Softenon) </li></ul><ul><li>etcetera, etcetera, etcetera </li></ul>
    17. 18. The Lancet, 1961
    18. 19. LETTER TO THE EDITOR THALIDOMIDE AND CONGENITAL ABNORMALITIES Sir, Congenital disorders are present in approximately 1.5% of babies. In recent months I have observed that the incidence of multiple severe abnormalities in babies delivered of women who were given the drug thalidomide ('Distaval') during pregnancy,as an anti-emetic or as a sedative, to be almost 20%. Have any of your readers seen similar abnormalities in babies delivered of women who have taken this drug during pregnancy? McBride WG. The Lancet, December 16, 1961: page 1358
    19. 20. Dwarsdoorsnede onderzoek beschrijft een karakteristieke relatie tussen determinant en uitkomst op 1 moment in de tijd Causaliteit?
    20. 22. Voorbeeld dwardoorsnede onderzoek Polymorphisms of the LEP- and LEPR gene and obesity in patients using antipsychotic medication Gregoor et al J Clin Psychopharmacol (2009) Onderzoeksvraag: zijn polymorfismen in de LEPR geassocieerd met hoger BMI in antipsychotica gebruikers? Studie opzet: dwarsdoorsnede onderzoek
    21. 23. Voorbeeld : LEPR onderzoek Populatie: 200 antipsychotica gebruikers Determinanten: LEPR Q223R en LEP promoter 2548G/A SNP polymorfismen Uitkomst: BMI
    22. 24. ** p<0.05 Voorbeeld : LEPR onderzoek N BMI>30 Males QQ 30 6 (20%) QR 73 16 (21%) RR 31 8 (26%) Females QQ 17 12 (71%) ** QR 39 15 (39%) QR 10 4 (40%)
    23. 25. Observational Cohort <ul><li>Group of individuals with common inclusion criteria is followed over time until an endpoint occurs. </li></ul>
    24. 26. Cohort study / Follow-up study Study population Exposed Non-exposed Disease + Disease + Disease - Disease -
    25. 27. Voorbeeld cohort onderzoek <ul><li>Zijn patiënten die van specialité naar generiek antihypertensivum switchen minder therapietrouw? </li></ul><ul><li>Blootstelling: switch </li></ul><ul><li>Uitkomst: therapitrouw </li></ul>
    26. 28. Switchers: 13,6% therapie-ontrouw Niet switchers: 18,7% therapie-ontrouw Van Wijk et al 2006
    27. 29. A cohort study <ul><li>RR (myocardial infarction)* </li></ul><ul><li>Untreated normotensive and hypertensive men 1.0 (reference) </li></ul><ul><li>Treated hypertensive men DBP  90 mmHg 3.8 (1.3-11.0) </li></ul><ul><li>Treated hypertensive men DBP>90 mmHg 1.1 (0.5-2.6) </li></ul><ul><li>* adjusted for previous MI, CVA, IHD, IC, diabetes, SBP, duration of antihypertensive therapy, hypercholesterolemia, hypertriglyceridaemia, creatinin, obesity, use of cardiac glycosides, smoking. </li></ul><ul><li>Conclusion: In men treated for hypertension, DBP should not be reduced to lower than 90 mmHg </li></ul>Merlo J, et al. BMJ 1996;313:457-61.
    28. 30. Another cohort study <ul><li>RR (stroke) </li></ul><ul><li>Untreated “Candidates”* for treatment 1.0 (reference) </li></ul><ul><li>Treated Crude RR 0.49 (0.32-0.76) </li></ul><ul><li>Adjusted RR* 0.61 (0.39-0.97) </li></ul><ul><li>** Adjusted for age, sex, diabetes, total cholesterol, BMI, smoking, history of CVD </li></ul><ul><li>* Candidates for treatment defined according to Dutch guidelines on treatment of hypertension taking into account multifactorial risk of cardiovascular disease </li></ul>Klungel et al. Epidemiology 2001;12:339-34 4.
    29. 31. Frequency measures cohort study (P1 personyears) (P0 personyears) A1 A0 Exposure No Exposure Disease Disease No disease Time Time No disease (B1) (B0)
    30. 32. Frequency measures <ul><li>Incidence </li></ul><ul><ul><li>Cumulative incidence (CI) </li></ul></ul><ul><ul><li>Incidence rate (IR) </li></ul></ul>
    31. 33. Risk disease + | exposure + = A1 / N1 = CI 1 Risk disease + | exposure - = A0 / N0 = CI 0 Frequency measures cohort study Disease No disease Total Exposure + A1 B1 N1 - A0 B0 N0
    32. 34. Force of morbidity | exposure + = A1 / P1 = IC 1 Force of morbidity | exposure - = A0 / P0 = IC 0 Frequency measures cohort study Disease Personyears Exposure + A1 P1 - A0 P0
    33. 35. Effect measures cohort study
    34. 36. Pill and Deep Venous Thrombosis <ul><li>Risk no pill = 3.9 per 100 000 py </li></ul><ul><li>Risk pill gen. 2 = 10.3 per 100 000 py </li></ul><ul><li>Risk pill gen. 3 = 21.3 per 100 000 py </li></ul><ul><li>RR 2/3 = 2.07 </li></ul><ul><li>RV 2/3 = 11.0 per 100 000 py </li></ul><ul><li>AR 2/3 = 52% </li></ul><ul><li>‘ NNH’ 2/3 = 9091 per year </li></ul><ul><li>Lancet 1995; 346: 1582 - 1588 </li></ul>
    35. 37. Analysis cohort study <ul><li>Survival analysis </li></ul><ul><ul><li>Kaplan Meier (CI) </li></ul></ul><ul><ul><li>Cox regression (I) </li></ul></ul><ul><ul><ul><li>Proportional hazards model: </li></ul></ul></ul><ul><ul><ul><li>ln (Inc) = h0(t) + b1 x X1 + b2 x X2 + … + b1 x Xi </li></ul></ul></ul><ul><ul><ul><li>Interpretation: e b1 =HR x1 (adjusted for X2 .. Xi) </li></ul></ul></ul>
    36. 38. Kaplan Meier
    37. 39. Prospective vs. retrospective Cohort Studies <ul><li>Prospective Cohort Studies </li></ul><ul><ul><li>Time consuming, expensive </li></ul></ul><ul><ul><li>More valid information on exposure </li></ul></ul><ul><ul><li>Measurements on potential confounders </li></ul></ul><ul><li>Retrospective Cohort Studies </li></ul><ul><ul><li>Quick, cheap </li></ul></ul><ul><ul><li>Appropriate to examine outcome with long latency periods </li></ul></ul><ul><ul><li>Admission to exposure data </li></ul></ul><ul><ul><li>Difficult to obtain information of exposure </li></ul></ul><ul><ul><li>Risk of confounding </li></ul></ul>
    38. 40. Selection of the Exposed Population <ul><li>Sample of the general population: </li></ul><ul><ul><li>Geographically area, special age groups, birth cohorts (Framingham Study) </li></ul></ul><ul><li>A group that is easy to identify: </li></ul><ul><ul><li>Nurses health study </li></ul></ul><ul><li>Special population (often occupational epidemiology): </li></ul><ul><ul><li>Rare and special exposure </li></ul></ul><ul><ul><li>Permits the evaluation of rare outcomes </li></ul></ul>
    39. 41. Selection of the Comparison Population <ul><li>Internal Control Group </li></ul><ul><ul><li>Exposed and non-exposed in the same Study population (Framingham study, Nurses health study) </li></ul></ul><ul><ul><ul><li>Minimise the differences between exposed and non-exposed </li></ul></ul></ul><ul><li>External Control Group </li></ul><ul><ul><li>Chosen in another group, another cohort (Occupational epidemiology: Asbestosis vs. cotton workers) </li></ul></ul><ul><li>The General Population </li></ul>
    40. 42. Follow up study versus RCT <ul><li>Similarities </li></ul><ul><ul><li>Use of same measures of frequency and association (RR, RD, AR, RRR, NNT, NNH) </li></ul></ul><ul><ul><li>Use of same analytical techniques (“survival” analysis: Kaplan Meier curves and Cox proportional hazard) </li></ul></ul><ul><li>Differences </li></ul><ul><ul><li>Follow-up vs. RCT: no randomisation and no blinding </li></ul></ul><ul><ul><ul><li>(outcome measurement sometimes blinded) </li></ul></ul></ul>Follow-up studies more vulnerable to bias
    41. 43. Cohort study / Follow-up study Study population Exposed Non-exposed Disease + Disease + Disease - Disease -
    42. 44. Case-control study Study Population Cases Controls Exposed Non-exposed Exposed Non-exposed
    43. 45. Example case-control study <ul><li>What is the risk on breast cancer with the use of SSRI antidepressants? </li></ul><ul><li>Cases: women with breastcancer </li></ul><ul><li>Controles: women with no breastcancer </li></ul><ul><li>Exposure: SSRIs </li></ul>
    44. 46. Coogan et al. Am J Epidemiol 2005
    45. 47. Meaning of odds and odds ratio ? <ul><li>Term from English gambling “4 to 1” </li></ul><ul><li>Odds means chance of succes (Ps) / chance of no success (Pns) </li></ul><ul><li>Pns = 1-Ps </li></ul><ul><li>Odds = Ps / 1-Ps </li></ul><ul><li>Ps = 1/5 =0,2 => odds = 0,2 / 0,8 = 0.25 (4 to 1) </li></ul><ul><li>In epidemiology ‘Exposure odds’ of interest </li></ul>
    46. 48. Case Control Exposure + a b - c d a+c b+d Exposure odds among cases = a/c Exposure odds among controls = b/d Exposure Odds ratio (OR) = (a/c) / (b/d) = (a*d) / (b*c)  RR Calculation OR
    47. 49. Rofecoxib and risk of MI <ul><li>Nested Case Control design: </li></ul><ul><li>9218 MI cases of whom 93 used of rofecoxib < 3 months ago </li></ul><ul><li>86349 controls, of whom 634 used of rofecoxib < 3 months ago </li></ul><ul><li>MI control </li></ul><ul><li>Rofecoxib + 93 634 </li></ul><ul><li>- 9125 85715 </li></ul><ul><li>OR (MI)= 93x85715 / 634x9125 = 1.38 </li></ul><ul><li>BMJ 2005;330:1366 </li></ul>
    48. 50. Selection of cases <ul><li>Establish strict diagnostic criteria for the outcome: </li></ul><ul><ul><li>Examples: </li></ul></ul><ul><ul><li>Type 1 diabetes in children: severe symptoms, very high BG, marked glycosuria, and ketonuria. </li></ul></ul><ul><ul><li>Type 2 diabetes: few if any symptoms, Slightly elevated BG, diagnosis “complicated”. </li></ul></ul>
    49. 51. Selection of cases <ul><li>Population-based cases: include all subjects or a random sample of all subjects with the disease at a single point or during a given period of time in the defined population: </li></ul><ul><ul><li>Disease registers </li></ul></ul><ul><li>Hospital-based cases: </li></ul><ul><li>All patients in a hospital department at a given time </li></ul>
    50. 52. Selection of Controls <ul><li>Principles of Control Selection: </li></ul><ul><li>Study base: </li></ul><ul><ul><li>Controls can be used to characterise the distribution of exposure </li></ul></ul><ul><li>Comparable-accuracy </li></ul><ul><ul><li>Equal reliability in the information obtained from cases and controls  no systematic misclassification </li></ul></ul><ul><li>Overcome confounding </li></ul><ul><ul><li>Elimination of confounding through control selection  matching or stratified sampling </li></ul></ul>
    51. 53. Selection of Controls <ul><li>General population controls: </li></ul><ul><ul><li>registries, households, telephone sampling </li></ul></ul><ul><ul><li>costly and time consuming </li></ul></ul><ul><ul><li>recall bias </li></ul></ul><ul><ul><li>eventually high non-response rate </li></ul></ul><ul><li>Hospitalised controls: </li></ul><ul><ul><li>Patients at the same hospital as the cases </li></ul></ul><ul><ul><li>Easy to identify </li></ul></ul><ul><ul><li>Less recall bias </li></ul></ul><ul><ul><li>Higher response rate </li></ul></ul>
    52. 54. Ascertainment of outcome and exposure status <ul><li>External sources: </li></ul><ul><ul><li>Death certificates, disease registries, Hospital and physicians records etc. </li></ul></ul><ul><li>Internal sources: </li></ul><ul><ul><li>Questionnaires and interviews, information from a surrogate (spouses or mother of children), biological sampling( e.g. antibody) </li></ul></ul>
    53. 55. Data Collection External Data Sources Internal Data Sources Exposure Hospital records, employers Questionnaires, physical examinations, and/or blood tests, other diagnostic tests Event Disease registries, death certificates, physician and hospital records Questionnaires, physical examinations, and/or blood tests, other diagnostic tests Confounder Hospital records registries Questionnaires, physical examinations
    54. 56. Strengths in Cohort vs. Case-control? <ul><li>Cohort study </li></ul><ul><li>Rare exposure </li></ul><ul><li>Examine multiple effects of a single exposure </li></ul><ul><li>Minimizes bias in the in exposure determination </li></ul><ul><li>Direct measurements of incidence of the disease </li></ul><ul><li>Case-control study </li></ul><ul><li>Quick, inexpensive </li></ul><ul><li>Well-suited to the evaluation of diseases with long latency period </li></ul><ul><li>Rare diseases </li></ul><ul><li>Examine multiple etiologic factors for a single disease </li></ul>
    55. 57. Limitations in Cohort vs. Case-control? <ul><li>Cohort study </li></ul><ul><li>Not rare diseases </li></ul><ul><li>Prospective: Expensive and time consuming </li></ul><ul><li>Retrospective: in adequate records </li></ul><ul><li>Validity can be affected by losses to follow-up </li></ul><ul><li>Case-control study </li></ul><ul><li>Not rare exposure </li></ul><ul><li>Incidence rates cannot be estimated unless the study is population based </li></ul><ul><li>Selection Bias and recall bias </li></ul>
    56. 58. Validiteit + Precisie -
    57. 59. Validiteit - Precisie +
    58. 60. Validiteit + Precisie +
    59. 61. Validiteit - Precisie -
    60. 62. Precisie en validiteit (vertekende resultaten) <ul><li>Toevallige fouten: </li></ul><ul><li>‘ random error’ (precisie) </li></ul><ul><li>steekproef </li></ul><ul><li>Systematische fouten: </li></ul><ul><li>‘ systematic error’ (validiteit) </li></ul><ul><li>bias en confounding </li></ul>
    61. 63. Power and precision
    62. 64. Sample size in case-control study of OC use and MI among women <ul><li>Assuming proportion of current OC use of 10%; </li></ul><ul><li>Power: 1-  (type II error) = 80% </li></ul><ul><li>Precision:  (type I error) = 5% </li></ul>
    63. 65. Sample size requirement in RCT <ul><li>baseline risk number required </li></ul><ul><li>side effect in each group </li></ul><ul><li>in control group </li></ul><ul><li>50% 14 </li></ul><ul><li>25% 77 </li></ul><ul><li>10% 266 </li></ul><ul><li>5% 582 </li></ul><ul><li>1% (liver dysfunction) 3,104 </li></ul><ul><li>0.1% (hepatitis) 31,483 </li></ul><ul><li>0.01% (cholestatic jaundice) 315,268 </li></ul>
    64. 66. The likelihood of observing an adverse drug reaction in 2,000 patients Threshold for ADR Probability 1 / 500 0.98 (Lymphoma From Azathioprine) 1 / 1,00 0.86 (Eye Damage From Practolol) 1 / 10,000 0.18 (Anaphylaxis From Penicillin) 1 / 50,000 0.04 (Aplastic Anemia From Chloramphenicol) Lembit Rägo, WHO Upsala
    65. 67. Validiteit van onderzoek <ul><li>Komen de bevindingen uit het onderzoek overeen met de werkelijkheid? </li></ul><ul><li>Externe en interne validiteit </li></ul><ul><ul><li>Externe validiteit: representativiteit en non-response </li></ul></ul><ul><ul><li>Interne validiteit: selectie bias, informatiebias en confounding bias </li></ul></ul>
    66. 68. Soorten van selectie- en informatiebias <ul><li>Channeling bias </li></ul><ul><li>Referal bias </li></ul><ul><li>Diagnostic bias </li></ul><ul><li>Observer bias </li></ul><ul><li>Recall bias </li></ul><ul><li>Response bias </li></ul>selectie informatie
    67. 69. Information bias (follow-up) <ul><li>Question: do patients who are treated for Hodgkin’s disease have a higher chance of a second tumor ? </li></ul><ul><ul><li>Compared incidence of cancer in a group of treated Hodgkin patiënts with incidence of cancer in general population (matching on age and gender) </li></ul></ul>Information bias (if RR = 1 probably no bias; if RR>1 cave bias)
    68. 70. Selecti on bias (cohort) <ul><li>Observation a l cohort stud y </li></ul><ul><li>RR (myocardial infarction)* </li></ul><ul><li>Untreated normotensive and hypertensive men 1.0 (reference) </li></ul><ul><li>Treated hypertensive men DBP  90 mmHg 3.8 (1.3-11.0) </li></ul><ul><li>Treated hypertensive men DBP>90 mmHg 1.1 (0.5-2.6) </li></ul><ul><li>* adjusted for previous MI, CVA, IHD, IC, diabetes, SBP, duration of antihypertensive therapy, hypercholesterolemia, hypertriglyceridaemia, creatinin, obesity, use of cardiac glycosides, smoking. </li></ul><ul><li>Conclusion: In men treated for hypertension, DBP should not be reduced to lower than 90 mmHg </li></ul>Merlo J, et al. BMJ 1996;313:457-61.
    69. 71. Selecti on bias (cohort) <ul><li>Observation a l cohort stud y in the Netherlands </li></ul><ul><li>RR (stroke) </li></ul><ul><li>Untreated “Candidates”* for treatment 1.0 (reference) </li></ul><ul><li>Treated Crude RR 0.49 (0.32-0.76) </li></ul><ul><li>Adjusted RR* 0.61 (0.39-0.97) </li></ul><ul><li>** Adjusted for age, sex, diabetes, total cholesterol, BMI, smoking, history of CVD </li></ul><ul><li>* Candidates for treatment defined according to Dutch guidelines on treatment of hypertension taking into account multifactorial risk of cardiovascular disease </li></ul>Klungel et al. Epidemiology 2001;12:339-34 4.
    70. 72. Case control Time Time Exposure No exposure Exposure No exposure Case (disease) Control (no disease)
    71. 73. Selection of controls <ul><li>Smoking and leukemia </li></ul><ul><ul><ul><li>cases: patients with leukemia </li></ul></ul></ul><ul><ul><ul><li>controls: patients in hospital for other disease </li></ul></ul></ul><ul><li>Patients hospitalized for CVD as control ? </li></ul><ul><li>Patients with history of CVD, not hospitalized for CVD </li></ul><ul><ul><ul><li>Smoking => CVD </li></ul></ul></ul>
    72. 74. Information bias (case-control) <ul><li>Drugs and congenital malformation </li></ul><ul><li>Cases : children with congenital malformation </li></ul><ul><li>Controls : children without malformation </li></ul><ul><li>Exposure: use of drugs </li></ul>
    73. 75. Selection bias (case-control) I <ul><li>Oral contraceptives and DVT </li></ul><ul><li>It was published (prospective follow up) in the 60’s after introduction of OAC that OAC increase the risk for DVT 3 times </li></ul><ul><li>New study planned: case control design </li></ul><ul><ul><li>Cases? </li></ul></ul><ul><ul><li>Controls? </li></ul></ul>
    74. 76. Selection bias (case-control) II <ul><li>Women with pain in leg </li></ul><ul><ul><li>Physician asks about use of the pil </li></ul></ul><ul><ul><li>If use of pil, refer to hospital, otherwise not. </li></ul></ul><ul><li>RR DVT OC use  </li></ul><ul><li>Solution ? </li></ul>
    75. 77. Methoden om voor vertekende resulaten te corrigeren <ul><li>Restrictie / Stratificatie </li></ul><ul><li>Mantel Haenszel </li></ul><ul><li>Matchen </li></ul><ul><li>1:1 of proportioneel </li></ul><ul><li>Mathematische modellen </li></ul><ul><li>verschillende regressietechnieken (bij patiënt controle logische regressie ; bij follow-up Cox of Poisson regressie ) </li></ul>
    76. 78. Risk assessment
    77. 82. Registration of a drug is only the beginning of safety research email: e.r.heerdink@uu.nl twitter: @robheerdink www.slideshare.net/robheerdink

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