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TAs for PubH 7420

TAs for PubH 7420 . Yun Bai – baix0022@umn.edu Wednesday, 10AM – Noon Kristin Cunanan – cunan001@umn.edu Friday, 3-5PM Debashree Ray – rayxx267@umn.edu Monday 3-5PM. Books on Reserve. Pocock : Clinical Trials. A Practical Approach.

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TAs for PubH 7420

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  1. TAs for PubH 7420 YunBai – baix0022@umn.edu Wednesday, 10AM – Noon Kristin Cunanan – cunan001@umn.edu Friday, 3-5PM Debashree Ray – rayxx267@umn.edu Monday 3-5PM

  2. Books on Reserve • Pocock: Clinical Trials. A Practical Approach. • Meinert: Clinical Trials. Design, Conduct and and Analysis Reading Room – 4th floor Mayo

  3. General Methods of Investigation 1. Chance observations 2. Case histories • individual cases • case series 3. Uncontrolled trials of an intervention 4. Cross-sectional (naturalistic) studies 5. Case-control studies 6. Prospective follow-up studies 7. Randomized clinical trial No planned concurrent comparison group

  4. Examples of Case-Control Studies 1. Multi-Center study of SIDS (Hoffman H, Ann NY AcadSci, 1988) • Influenza vaccine effectiveness (Treanor JJ et al, CID, 2012) • Coffee drinking and CHD • Soluble biomarkers and all-cause mortality (nested case-control study)

  5. Example Treanor JJ et al. Effectiveness of seasonal influenza vaccines in the United States during a season with circulation of all three vaccine strains. CID 55:951-959, 2012. Purpose: To assess vaccine effectiveness during the 2010-2011 season.

  6. Design: Case-control study Cases: Persons in 5 communities (4 states) seeking care for an acute respiratory illness (ARI) with positive respiratory specimens. Controls:Persons in same communities with ARI with negative respiratory specimen Factor: At least 1 dose of seasonal influenza vaccine at least 14 days before symptom onset.

  7. Case-Control StudyVaccine Effectiveness, CID, 20126. Test Neg. Controls Test Pos. Cases Vaccine 317 1958 2275 No Vaccine 711 1726 2437 4,712 3684 1028 Vaccine use among cases = 317 / 1028 = 31% Vaccine use among controls = 1958 / 3684 = 53% Odds ratio (OR) = (317x1726)/(1958x711)= 0.39

  8. Vaccine Effectiveness (VE) • OR = 0.39 • VE = (1-OR) x 100 = 61%; 95% CI (55-66) • Adj VE = 60% ; 95% CI (54-66) • Adjusted for study site, age, race, insurance, and high risk condition

  9. Example Hennekens et al. Coffee drinking and death due to coronary heart disease. NEJM 294:633-36, 1976. Purpose: To investigate the relation between coffee drinking and death due to CHD.

  10. Design: Individually matched case-control study Cases: Married, white men, aged 30-70 who died from CHD within 24 hours of symptom onset according to death certificate Controls:Age, sex, neighborhood matched Agent: Coffee consumption as assessed by interview with wife 2-8 weeks after death Consumption 3 months prior to death or interview

  11. Case-Control StudyHennekens et al. Coffee drinking and death due to coronary heart disease. NEJM, 1976. Neighborhood Controls CHD Cases 1+ cups/day 500 485 985 None 149 164 313 1,298 649 649 Prevalence of coffee drinking among cases = 500 / 649 = 77% Prevalence of coffee drinking among controls = 485 / 649 = 75%

  12. Matched Analysisfor Coffee Study Cases 1+ cups/day None 1+ cups/day 359 126 485 Controls None 141 23 164 500 149 649 ^ 141 126 Odds Ratio (OR) = = 1.12

  13. Other Considerations in Interpreting Findings from Observational Studies Bias (def.) A systematic error usually introduced by investigator and/or patient which leads to incorrect estimates of the association between a risk factor and a disease endpoint. • Case and control selection and recall bias are common problems in case-control studies

  14. Possible Sources of Bias in Vaccine and Coffee Case-Control Studies 1. Identification of cases and controls 2. Interviewer 3. Vaccine receipt, and wife’s report or memory of spouse’s coffee consumption

  15. Nested Case-Control Study: SMART Study Baseline plasma samples were identified for patients who died (85patients) and for two matched controls for each death (170 patients). Matching was on country, age (+/- 5years), gender and approximate date of randomization (+/- 3 months). Conditional logistic for matched studies used to estimate odds ratios (OR) for mortality with participants in lowest quartile as reference. Adjusted OR consider covariates corresponding to age, race, ART, HIV RNA, CD4+ count, BMI, and total/HDL cholesterol at baseline, smoking, diabetes, hep B/C co-infection, use of lipid and BP lowering medication PLoS Medicine 2008; 5(10) e203

  16. Nested Case Control Design 0 Time Axis Two matched controls for every case were chosen. Follow-up for all members of the cohort (horizontal white lines) begins at randomization (zero-time axis).

  17. Cohort Study Example: Framingham Heart Study Goal: 6,000 men and women aged 30-59 estimated to yield 2,000 new cases by the end of the 20th century Selection of Sample • Annual publication by town of Framingham • Stratified by family size and location of residence • Sample unit - family (cluster) • Systematic sampling within stratum

  18. Result • Acceptance rate = 69% • Eventual “starting” sample 4469 respondents + 740 volunteers 5209 Potential for bias? • Prevalence data • Association of risk factors with disease incidence

  19. Another Cohort Study Example Shekelle et al. MRFIT behavior pattern study: Type A behavior and incidence of coronary heart disease. Am J Epid 122:559, 1985. Question: Is type A behavior associated with an increased incidence of CHD. Design: Prospective follow-up study – cohort study within a randomized clinical trial

  20. Overview of MRFIT Behavior Pattern Study Risk factor: Behavior pattern assessed by interview (4 point scale) • Each interview taped and reviewed • Quality assurance (J Chronic Dis 1978; 32:293-305) Endpoint: CHD death or non-fatal MI in 7 years • Mortality review committee • Blinding assessments Study subjects: MRFIT men (aged 35-37 with risk factors for CVD)

  21. Prospective Observational Study No CHD Event CHD Event Type A 94 2,220 2,314 Type B 35 761 769 129 2,981 3,110 ^ 94 (761) 35 (2,220) Odds Ratio (OR) = = 0.92

  22. Prospective Observational StudyMRFIT Behavior Pattern Study. AM J Epi, 1985. No. Person Years of Follow-up No. CHD Events Type A 94 15,973 Type B 35 5,514 129 21,487 Probability of CHD in 7 years among Type A participants = (94 / 15,973) x 1,000 = 5.9 For Type B = (35 / 5,514) x 1,000 = 6.3 ^ ^ 5.9 6.3 RR = = 0.94; Adjusted RR = 0.87

  23. Conclusion “Type A behavior was not associated with CHD in MRFIT … further study is needed.”

  24. The MRFIT BehaviorPattern Study “Employed ad-hoc, poorly chosen, inadequately trained, non-professional clerks to administer the structured interview?” “The widely disseminated negative findings of the MRFIT study have delayed the introduction of a procedure that could have prolonged the lives of hundreds of thousands of patients with CHD.” Source: Friedman M. Am Heart J, 115:950-35, 1988.

  25. Men Screened for the Multiple Risk FactorIntervention Trial (MRFIT) • 361,622 men aged 35-57 screened in 1973-75; 12,866 were ultimately randomized • Mortality follow-up using National Death Index (NDI) • Large cohort study

  26. Classification of BP*JNC VII Criteria Category Systolic Diastolic Normal <120 AND <80 Pre-hypertension 120-139 OR 80-89 Hypertension Stage 1 140-159 OR 90-99 Stage 2 160+ OR 100+ *May 2003; http://www.nhlbi.nih.gov/guidelines/hypertension

  27. Reduced Risk of CVD Death over 30 Years Associated with Pre-Hypertension Compared to Stage 1 Hypertension: Role of Chance Hazard Ratio (High Normal/Stage1) No. CVD Deaths HR 95% CI P-value 1st 500 43 0.39 0.19 to 0.80 0.01in Minneapolis All of 2992 0.57 0.52 to 0.62 <.00001Minneapolis All 22 sites 34,149 0.57 0.56 to 0.59 <.00001

  28. Reduced Risk of CVD Death Associated with High Normal BP Compared to Stage 1 Hypertension: Role of Confounding Factors (Those Measured) Unadjusted and AdjustedHazard Ratio (HR) HR 95% CI Unadjusted 0.57 0.56 to 0.59 Adjusted for age 0.64 0.62 to 0.65 Adjusted for other 0.65 0.64 to 0.67risk factors

  29. Observational Studies Are Also Used to Study the Safety and Effectiveness of Treatments • Sometimes there is not a good alternative (e.g., long-term safety of approved drugs) • Safer if magnitude of effect is large since bias can dominate small effects • There are many examples where observational studies were wrong (e.g., antioxidant vitamin intake and hormone replacement therapy) • Observational studies are important for planning/motivating trials. • Moving from observational studies to trials is all about timing: • Strike to soon and you may fail to answer the right question. • Procrastinate, and practice patterns may be so ingrained that it is impossible to conduct a trial.

  30. Cohort Study Considerations • Representativeness of sample • Confounding • Bias due to incomplete endpoint ascertainment (e.g., differential lost-to-follow-up rates) – missing data • Protocol for risk factor (predictor) assessment • Number of participants with outcome of interest (sampling variability)

  31. Randomized Clinical Trial • A prospective study in which the investigators determine who receives the intervention or agent and who does not by a random process • A carefully planned manipulation of a “natural” state • “A prospective study comparing the effect and value of intervention(s) against a control in human beings”

  32. Some Resources for Finding Trials • Registered trials • www.clinicaltrials.gov • Trial registry developed in England • www.controlled-trials.com • Published trials • www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed\

  33. Essential Components of a Randomized Clinical Trial • Clearly stated question/hypothesis • Statistical design (sample size, power) to address hypothesis • Definition of target population • A control group • Random method of treatment assignment after informed consent • Excellent follow-up and unbiased endpoint ascertainment • Monitoring plan

  34. Aspirin Myocardial Infarction Study (AMIS) • Randomized double-blind placebo-controlled study Purpose: To determine whether regular use of aspirin results in a reduction in 3-year mortality among patients with at least one documented MI (secondary prevention trial)

  35. Risk Indicators According to Aspirin Use in Women Aged 34-59 Years Aspirin / Week 0 1 - 3 4 - 6 7 - 14 ≥ 15 No. 52,630 15,540 7,518 7,352 4,998 Age (years) 45.9 45.7 45.4 46.8 47.8 Hypertension (%) 15.0 13.2 16.3 17.9 17.7 Smokers (%) 28.2 28.9 30.6 30.2 30.8 High cholesterol (%) 5.0 4.6 4.9 6.1 5.9 Manson et al. A prospective study of aspirin use and primary prevention of cardiovascular disease in women. JAMA, 1991. More aspirin/week associated with greater prevalence of risk factors.

  36. AMIS Overview Study subjects: • men and women 30-69 • no contraindication to aspirin • with a previous documented MI (secondary prevention) Treatments: - aspirin (0.5 grams twice daily) - placebo Follow-up - for at least 3 years Endpoint: - total mortality (most deaths expected to be due to cardiovascular disease)

  37. AMIS: Characteristics at Baseline Placebo (N=2257) Aspirin (N=2267) Men (%) 88.4 89.4 White (%) 91.7 91.5 SBP (mmHg) 127.9 128.2 Cholesterol (µ mol/l) 6.1 6.1 Age (years) 54.8 54.8 Cigarette smoker (%) 27.5 27.2 No. MI’s 1.2 1.2 Note difference from study by Manson.

  38. AMIS: Total Mortality Findings Survivors Deaths Aspirin 245 2,022 2,267 Placebo 219 2,038 2,257 4,524 464 4,060 ^ (RR) = 1.11, P = 0.20 ^ Adj. (RR) = 1.05, P = 0.50

  39. Conclusion No beneficial effect of aspirin • at this stage of Rx • at this dose • when given for 3 years • on total mortality (some reduction in non-fatal MI and stroke was found) “Aspirin is not recommended for routine use in patients who have survived an MI”

  40. Other Notable Findings 1. Vital status of all but 9 patients ascertained 2. Average missed visit rate approximately 6% for both groups 3. Average 1.6 capsules per day taken; platelet aggregation and urine tests for compliance consistent with capsule counts 4. Side effects more common with aspirin 5. Multiple outcomes assessed

  41. Antiplatelet Regimensand CVD Morbidity and Mortality Oddsreduction (SD) Trialsanalysed AntiplateletRegimen Adjustedcontrols* Antiplatelet Cardiff-I Aspirin 58/615 76/624 25% ± 16 Cardiff-II Aspirin 129/847 185/878 32% ± 10 Paris-I A or A+Dip 244/1620 4(77/406)* 25% ± 13 Paris-II A+Dip 154/1563 218/1565 32% ± 9 AMIS Aspirin 395/2267 427/225710% ± 7 CDP-A Aspirin 88/758 110/771 21% ± 14 GAMIS Aspirin 39/317 49/309 25% ± 20 ART Sulphin 102/813 130/816 24% ± 12 ARIS Sulphin 38/365 57/362 37% ± 18 Micristin Aspirin 65/672 106/666 43% ± 13 Rome Diphrid 9/40 19/40 66% ± 28 Adjusted* total for 1321/9877 1685/9914 25% ± 4all prior MI trials * The actual PARIS-I control result (which is used for calculation of O-E) is 77/406, but to match the PARIS-I treatment group size this control contributes fourfold (308/1624) to the adjusted total number of events and of patients. This adjustment has no effect on the calculations of statistics. Reference: Peto R, et al., J Clin Epid, 1:12-40, 1995.

  42. Hierarchy of Evidence Coherence of evidence from multiple sources Systematic review of well-designed, large randomized trials Strong evidence from one large randomized trial Systematic review of small trials (e.g., surrogate outcome studies) Systematic review of from well-designed cohort studies Strong evidence from one cohort study Unsystematic observations (expert opinions) Adapted from Devereaux PJ et al, Evidence-Based Cardiology, 2nd Edition, BMJ Books, 2003.

  43. Recommendations on Aspirin • Aspirin is beneficial for secondary prevention (benefits clearly outweigh risks) • For primary prevention, the picture is not so clear based on several large trials: • British Doctor’s Study • Physicians’ Health Study • Thrombosis Prevention Trial • Hypertension Optimal Treatment Trial • Primary Prevention Project • Women’s Health Study

  44. Recent Recommendations • Antithrombotic Trialists’ Collaboration (Lancet 2009) • “In primary prevention without disease, aspirin is of uncertain value as the reduction in occlusive events needs to be weighed against any increase in major bleeds.” • U.S. Preventive Task Force (Ann Intern Med 2009) • Encourage men age 45-79 to use aspirin if potential benefits of MI reduction outweigh bleeding harm; encourage women aged 45-79 to use aspirin if potential ischemic stroke reduction outweigh bleeding harm; do not use < 45 and insufficient evidence > 80 years.

  45. Observation / Experiment “If important alternative hypotheses are compatible with available evidence, then the question is unsettled, even if the evidence is experimental. But, if only one hypothesis can explain all the evidence, then the question is settled, even if the evidence is observational.” Cornfield, J. Principles of research. Johns Hopkins University, Department of Biostatistics, Paper No. 325.

  46. Important Steps in Any Study • State objectives • Ensure that sample size and power are adequate to address objectives (before you begin) • Define population to be studied (sampled) and method of sampling • Define data to be collected and methods of measurement • Careful monitoring of field work • Data analysis based on design (sampling plan)

  47. Summary • Consideration of bias and confounding variables is central in the interpretation of findings from observational studies • Since uncontrolled confounding threatens the validity of findings from observational studies, it is essential that in the design possible confounders be identified and measured • Data analyses should be aimed at quantifying the influence of confounding factors • Not all possible confounders are known and not all can be measured, thus designs which eliminate/minimize confounding are particularly important in studying small/moderate effects

  48. Methods for Control of Confounding Variables Design • Randomization • Stratification • Matching Analysis • Stratified analysis (post-stratification) • Direct method • Mantel-Haenszel • Regression analysis

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