Causal Inference or Truth in the Universe

1. Causal InferenceorTruth in the Universe Deborah Grady, MD, MPH Professor of Medicine Co-Director, CTSI Director, CTSI Training Programs

2. Framework • Untruth - spurious associations • chance (small sample size) • bias (selection and other biases) • Truth - real associations, not always causal • effect - cause • effect - effect (confounding) • cause - effect (truth in the universe)

3. Randomized Clinical Trials • Eliminate effect-cause and confounding • Major pitfalls • Low power • Not randomized • Unblinded • Incomplete follow-up

4. Estrogen and CHD in Women RQ: Does postmenopausal estrogen therapy reduce CHD risk in women? Design: Cross-sectional Subjects: 20 postmenopausal women - entire population of my Tuesday clinic Measurements: estrogen therapy (ever/never) self-report; CHD (yes/no) chart review

5. Estrogen and CHD in WomenCross-Sectional Study CHD No CHD E No E 1 4 5 9 15 6 20 7 13 RR = 0.5 95% CI 0.8-3.2; p = 0.5

6. Estrogen and CHD in Women RQ: Does estrogen therapy reduce CHD risk? Design: Case-control Cases: 1000 women admitted to SFGH over a 5-year period with discharge diagnosis of CHD (ICD-9 codes) Controls: 1000 women identified by random digit dialing in SF who report no CHD Measurements: CHD based on discharge diagnosis; estrogen therapy based on self-report

7. Estrogen and CHD in WomenCase-Control Study CHD No CHD E No E 200 300 500 700 1500 800 2000 1000 1000 OR = .58; 95% CI .47-.72; p = .01

8. Estrogen and CHD in Women RQ: Does estrogen therapy reduce CHD risk? Design: Case-control Cases: 1000 women admitted to Kaiser over a 5-year period with discharge diagnosis of CHD Controls: 1000 women admitted to Kaiser over the same 5-year period with no discharge diagnosis of CHD Measurements: CHD based on discharge diagnosis; estrogen therapy based on computerized pharmacy records

9. 130 370 500 630 1500 870 2000 1000 1000 OR = .25; 95% CI .20-.32; p = .001 Estrogen and CHD in WomenCase-Control Study CHD No CHD E No E

10. Confounding All CHD No CHD E 130 370 500 No E 870 630 1500 1000 1000 2000 OR = .25; p = .001 Age 50-64 Age 65-79 CHD No CHD CHD No CHD E 360 400 E 90 10 100 40 No E 60 540 600 No E 810 90 900 100 900 1000 900 100 1000 OR = 1.0; p = .9 OR = 1.0; p = .9

11. Interaction All CHD No CHD E 250 250 500 No E 750 750 1500 1000 1000 2000 OR = .1.0; p = 0.6 Age 50-64 Age 65-79 CHD No CHD CHD No CHD E 100 200 300 E 150 50 200 No E 300 400 700 No E 450 350 800 400 600 1000 600 400 1000 OR = .67; p = .04 OR = 2.3; p = .01

12. Controlling Confounding • Design stage • Matching • Specification • Randomization • Analysis stage • Stratification • Multivariate modeling

13. Estrogen and CHD in Women RQ: Does estrogen therapy reduce CHD risk? Design: Prospective cohort Subjects: 59,337 PM nurses followed for 16 years Measurements: Self-reported estrogen use; self-reported CHD events validated by chart review Analysis: Multivariate logistic regression - age, ethnicity, education, blood pressure, diabetes, smoking, alcohol, family history of CHD and hypercholesterolemia

14. Nurses’ Health Study HormonesNPYARCHDRR P-value Never 20,034 324,748 452 1.0 referent Past 12,503 150,238 195 0.8 0.06 Current 14,000 166,371 98 0.6 0.01 Grodstein, NEJM, 1996

15. RISK FOR CORONARY HEART DISEASE IN ESTROGEN USERS VS. NONUSERS CohortStudies Grodstein, 2000 • Falkeborn, 1992 • Wolf, 1991 • Henderson, 1991 • Sullivan, 1990 • Avila, 1990 • Criqui, 1988 • Petitti, 1987 • Bush, 1987 • Wilson, 1985 • Angiographic Studies McFarland, 1989 • Sullivan, 1988 • Gruchow, 1988 • Case-Control Studies Mann, 1994 • Rosenberg, 1993 • Croft, 1989 • Beard, 1989 • Szklo, 1984 • Ross, 1981 • Bain, 1981 • Adam, 1981 • Rosenberg, 1980 • Pfeffer, 1978 • Talbott, 1977 • Rosenberg, 1976 • RR = 0.65 Summary Relative Risk s • 0.01 0.1 1 10 Relative Risk

16. Potential Mechanisms for CHD Benefit of Estrogen Therapy • Improves lipoproteins • Reduces LDL 10-15% • Increases HDL 10-15% • Retards atherosclerosis • Prevents coronary vasoconstriction

17. Causality Estrogen and CHD in Women Observational findings • Strong association • Consistent association • Plausible biologic mechanism

18. Reasons to be Cautious • Observational findings susceptible to bias and confounding • Estrogen has known risks • (Was a) preventive therapy widely used among healthy women

19. 4 Important Features of RCTs Adequate Power Rule out chance associations Find clinically significant associations Randomization Comparability at baseline - Bias - Confounding Blinding Comparability during follow-up - Placebo effect - Differential outcome ascertainment - Co-intervention Complete Follow-up Comparability at the end of the trial

20. Power of the Placebo Arthroscopic debridement of the knee • In unblinded trials • reduced knee pain about 60% • In blinded trials, reduced knee pain about 60% • subjects who underwent debridement • subjects who underwent sham debridement Moseley et al, NEJM, 2002

21. Blinding to Avoid Differential Outcome Adjudication Canadian Cooperative MS Trial • 165 patients with multiple sclerosis • plasma exchange + cyclo + pred • sham plasma exchange + placebo meds • Outcome = structured neurologic exam by blinded and unblinded neurologists • More improvement with plasma exchange by unblinded, but not blinded assessment Noseworthy, Neurology, 1994

22. Blinding to Avoid Co-Intervention • Unintended effective interventions • participants use other therapy or change behavior • study staff, medical providers, family or friends treat participants differently • Nondifferential decreases power • Differential causes bias

23. Estrogen and CHD in Women RQ: Does estrogen therapy reduce CHD risk? Design: Randomized trial Subjects: 2500 PM women with CHD Intervention: Estrogen + progestin vs. placebo Measurements: Predictor = treatment outcome = CHD death or nonfatal MI

24. 50 450 500 1000 1250 250 1750 300 1450 RR = .5; p = .001 Estrogen and CHD in WomenRandomized Trial CHD No CHD HT No HT

25. Heart and Estrogen-progestin Replacement Study (HERS) • 2763 postmenopausal women < 80 years old with documented CHD and a uterus • Randomized to CEE 0.625 mg plus MPA 2.5 mg or identical placebo • Followed every 4 months for 4.2 years • Separate gynecology group managed bleeding • Outcome = nonfatal MI and CHD death

26. Randomized2,763 HERS Trial Profile Placebo1,383 Estrogen + Progestin1,380 Died - 123 Dead or completed follow-up - 91% Vital Status Known - 100% Died - 131 Dead or completed follow-up - 91% Vital Status Known - 100%

27. HERS: Baseline Characteristics HRTPlacebo Age (years) 67 67 White (%) 88 90 Current Smoker (%) 13 13 Diabetes (%) 19 18 Blood pressure (mmHg) 135 135 LDL-C (mg/dL) 145 145 BMI > 27 (kg/m2) 57 55 Prior estrogen use (%) 24 23

28. Cumulative % Years CHD Events in HERS R.H. = 1.0 (95% CI 0.8 to 1.2) Hulley, Grady, JAMA 1998

29. HERS: Primary Outcomes E+PPboRRp-value Total CHD events 172 176 1.0 0.9 CHD death 71 58 1.2 0.2 Non-fatal MI 116 129 0.9 0.5

30. HERS: Cardiovascular Outcomes HTPlacebo RH p-value (N=1380) (N=1383) CABG 88 101 0.9 .4 PTCA 164 175 0.9 .6 Unstable angina 103 117 0.9 .4 CHF 128 112 1.0 .6 PVD 94 108 0.9 .3 Stroke/TIA 108 96 1.1 .4

31. HERS vs. Observational Studies Why did the findings of HERS differ? • HERS design different • adverse effect of added progestin • no benefit in women with CHD • Observational findings wrong • selection bias - comparison groups differ • adherence bias

32. Women’s Health Initiative • 2 NIH-funded concurrent randomized trials in postmenopausal women • uterus - CE+MPA vs. placebo (16,606) • no uterus - CE vs. placebo (10,739) • Multiple outcomes • Planned follow-up 9 years • Both trials stopped early due to harm or lack of benefit

33. WHI Results Relative Risks *p-value < .05

34. Benefit of Adherence with Medication 5 Year Mortality (%) Adherence Clofibrate Placebo All 20 21 <80% pills 22 >80% pills 16 26 16 Coronary Drug Project, NEJM, 1980

35. Are Observational Studies Useless? • NO • generate important hypotheses • provide only answer if trial not feasible • generally produce correct answer • But bias and confounding always worrisome • Particularly problematic for interventions that require selection and adherence

36. Summary • Untruth - spurious associations • chance (small sample size) • bias (selection and other biases) • Truth - real associations, not always causal • effect - cause • effect - effect (confounding) • cause - effect (truth in the universe)

37. QUESTIONS??? Thank you!