1. 1 Classification Schemes for “Ways of Getting the Wrong Answer”  Szklo and Nieto –Bias »Selection Bias »Information/Measurement Bias –Confounding –Chance  Other Common Approach –Bias »Selection Bias »Information/Measurement Bias »Confounding Bias –Chance

2. 2 Confounding and Interaction  Confounding: one of the central problems in observational clinical research –What is it? What does it do? –What kind of variables act as confounders? –Which variables to consider as confounders? –Which variables not to consider as confounders?

3. 3 Smoking, Matches, and Lung Cancer  A tobacco company researcher believes that exposure to matches is the cause of lung cancer  He conducts a large case-control study to test this hypothesis

4. 4 Smoking, Matches, and Lung Cancer  Your colleague has located 1000 cases of lung cancer from a population-based registry, of whom 820 have a history of carrying matches.  Among 1000 reference (control) patients (selected randomly from the population and found to have normal chest x-rays), 340 carry matches.  Quantitate the relationship between matches and lung cancer in your colleague’s data.

5. 5 Matches and Lung cancer  Exposure odds ratio = (820/180) / (340/660) = disease odds ratio  OR = 8.8  95% CI (7.2, 10.9)

6. 6 Smoking, Matches, and Lung Cancer  You decide to look at the relationship between matches and lung cancer in the smokers separately from the non-smokers.  You find that among the 1000 cases, 900 are smokers and 810 (OF THE 900) carry matches.  Among the 1000 reference patients, 300 are smokers and 270 (OF THE 300) carry matches.  Draw the necessary stratified tables and calculate the relevant measure of association

7. 7 Smoking, Matches, and Lung Cancer Stratified Crude Non-SmokersSmokers OR crude OR CF+ = OR smokers OR CF- = OR non - smokers  OR crude = 8.8 (7.2, 10.9)  OR smokers = 1.0 (0.6, 1.5)  OR non-smoker = 1.0 (0.5, 2.0)

8. 8 Confounding: Smoking, Matches, and Lung Cancer  Illustrates how confounding can create an apparent effect even when there is no actual true effect  In the relationship between matches and lung cancer, smoking is a ________ factor or a ______________  Smoking _______ the relationship between matches and lung cancer

9. 9 Estes continues to be confounding puzzle Ray RATTO Friday, July 20, 2001 ©2001 San Francisco Chronicle Ray RATTO ©2001 San Francisco Chronicle SHAWN ESTES seemed loath to analyze his own performance last night, for fear that people would see the first three innings and use them to obscure the last four. But that's what made his outing so perfectly Estes-like -- an ongoing argument with himself that he eventually won. Well, an argument in which he held his own and his teammates won for him in the bottom of the ninth. Ramon Martinez lined a game-tying single with two outs, and Jeff Kent followed two batters later with a bases- loaded walk off Juan Acevedo to give the Giants a 2-1 victory against Colorado and move them to within 4 1/2 games of division leader Arizona. It was in many ways an eye-opening victory for a team that hadn't had one of this type for a while.

10. 10  Finding: “After an initial course of post-exposure prophylactic (PEP) medication following a sexual exposure to HIV infection, gay men reported a decrease in the practice of high-risk behavior over the following year.”  Reviewer: “Perhaps the men simply withheld the real amount of high-risk behavior they had in order to be eligible for future courses of PEP. How do you account for this confounding?”

11. 11 Smoking, Matches, and Lung Cancer  To be complete, you also decide to examine the relationship between smoking and lung cancer independent from the use of matches.  What tables should you construct to do this?

12. 12 Smoking, Matches, and Lung Cancer Stratified Crude Matches Absent Matches Present OR crude OR CF+ = OR matches OR CF+ = OR no matches  OR crude = 21.0 (16.4, 26.9)  OR matches = 21.0 (10.7, 41.3)  OR no matches = 21.0 (13.1, 33.6)

13. 13 Confounding: Smoking, Matches, and Lung Cancer  What is the effect of matches on the relationship between smoking and lung cancer? –Illustrates one important component in the requirements of a ____________________ (aka a _______________ factor)

14. 14 Confounding: Examples of Magnitude and Direction Stratified Crude Potential Confounder Absent Potential Confounder Present RR crude RR CF+ RR CF-

15. 15 Nightlights

16. 16 Nightlights and Myopia  Quinn et al. Nature 1999  Prevalence Ratio =

17. 17  Insert picture with nightlight off

18. 18 Nightlights and Myopia:  Two subsequent studies found no association –Zadnik et al. and Gwiazda et al. Nature, 2000

19. 19 Child’s Myopia Night Light Parental Myopia X X

20. 20  Insert picture with nightlight on again

21. 21 What kind of variables act as confounders?  Properties of a True Confounder –A true confounder (C) must be associated with: »the exposure (E) in question and »the disease (D) under study Confounder D D ANOTHER PATHWAY TO GET TO THE DISEASE ANOTHER PATHWAY TO GET TO THE DISEASE

22. 22 What kind of variables act as confounders?  Properties of a True Confounder –A true confounder (C) must be associated with: »the exposure (E) in question and »the disease (D) under study Confounder D D ANOTHER PATHWAY TO GET TO THE DISEASE ANOTHER PATHWAY TO GET TO THE DISEASE

23. 23 Lung Cancer Matches Smoking ? ?

24. 24 Properties of a True Confounder Refined Properties: Association with Exposure  A confounding variable can be either the cause of, the result of, or simply associated in a non- causal manner with the exposure in question Confounder D D

25. 25 C causes E ? [cardiovascular work-out]

26. 26 Mortality Poor Diet Poverty ? ? E causes C [access to care]

27. 27 Non-causal relationship between C and E CAD

28. 28 Properties of a True Confounder Refined Properties: Association with Exposure  A confounding variable must be associated with the exposure in question independent of its association with the disease in question. –It must be associated with the exposure not simply through its association with the disease (i.e. must be associated with the exposure among the non-diseased)

29. 29 H. pylori

30. 30 Properties of a True Confounder Refined Properties: Association with Disease  A confounding variable must be associated with the disease. –It need not be a “cause” of disease; it may merely be a marker for (i.e. associated with) a cause Confounder D D

31. 31 Early Mortality Hep B and C virus infection IDU ? ? C causes D

32. 32 C as a marker for D Unknown biologic factor(s)

33. 33 C as a marker for D Unknown biologic factor(s) Maternal Age Birth Order Down Syndrome

34. 34 Properties of a True Confounder Refined Properties: Association with Disease  A confounding variable must be associated with the disease independent of its association with the exposure in question »i.e. must be associated with the disease among the unexposed

35. 35 Lung Cancer Smoking Matches

36. 36 What is NOT a Confounder?  A variable that is an intermediate step in the causal path between the exposure in question and disease under study is not a confounding variable. E E D D factor I This factor is not a confounder

37. 37 CCR5 and HIV Disease Progression CCR5 (chemokine receptor) defect AIDS  CCR5 is the receptor for HIV  Is a defect in CCR5 associated with slower time to progression to AIDS?  HIV viral load is a powerful predictor of time-to-AIDS and is associated with CCR5 status  How should HIV viral load be handled?  CCR5 is the receptor for HIV  Is a defect in CCR5 associated with slower time to progression to AIDS?  HIV viral load is a powerful predictor of time-to-AIDS and is associated with CCR5 status  How should HIV viral load be handled? ? ?

38. 38 CCR5 and HIV Disease Progression Ioannidis et al. Ann Int Med 2001  Effect of CCR5 defect on development of AIDS  Stratified (adjusted) for HIV plasma viral load –Relative hazard: 0.82 (95% CI: 0.6 to 1.2)  Is adjusting for HIV viral load the right thing?

39. 39 CCR5 and HIV Disease Progression  A variable that is an intermediate step in the causal path between the exposure in question and disease under study is not a confounding variable. CCR5 (chemokine receptor) defect AIDS HIV viral load HIV viral load is clearly an intermediary factor Crude (unadjusted) association: Relative hazard: 0.71 (95% CI: 0.5 to 0.9) HIV viral load is clearly an intermediary factor Crude (unadjusted) association: Relative hazard: 0.71 (95% CI: 0.5 to 0.9)

40. 40 Exercise and CAD  Is HDL associated with exercise?  Is HDL associated with CAD?  When evaluating the relationship between exercise and CAD, is HDL a confounder or an intermediary? Exercise CAD HDL

41. 41 It depends on the pathway under investigation  If interest is in a pathway other than through HDL, then HDL is a confounder  Here, HDL is extraneous to pathway under study  Confounding factors are extraneous factors Exercise CAD not yet specified mechanism HDL ? ?

42. 42 Exercise and CAD  If there is only one pathway in question, then HDL is an intermediary variable.  e..g., Does exercise influence CAD risk in a newly studied population (elderly Asians)?  Hence, classification of HDL as confounder or intermediary depends upon the biological pathway under investigation Exercise CAD HDL HDL is not a confounder here

43. 43 What is NOT a Confounder?  Variables that are the RESULT of the disease, regardless of their association with the exposure are NOT confounders Confounder D D

44. 44 Lung CA Smoking Cough ? ? Cough is not a confounder. Do not adjust for it! Cough is not a confounder. Do not adjust for it!

45. 45 When Planning a Study, Which Factors Should be Considered as Potential Confounders?  Any factor for which prior evidence indicates it is a confounder and  In newer research areas: –factors known to be associated with the disease and which may be associated with exposure  When in doubt, plan on measuring ALL factors associated with the disease –i.e. If you don’t, you may regret it later

46. 46 Seeking cause of high Marin cancer rates Activists canvass residents to search for trends Sunday, November 10, 2002 Thousands of volunteers scattered across Marin County under baleful skies Saturday in an unprecedented grassroots campaign against the region's soaring cancer rate. Armed with surveys, some 2,000 volunteers went door to door in every neighborhood in the county, asking people whether they or anyone in their household has ever been diagnosed with cancer in Marin. The volunteers hope to collect enough money to hire an epidemiologist to analyze the data for use in future studies.

47. 47 Methods to Reduce Confounding  during study design: »Randomization »Restriction »Matching  during study analysis: »Stratified analysis

48. 48 Methods to Prevent or Manage Confounding D D D D or

49. 49 Methods to Prevent or Manage Confounding  By prohibiting at least one “arm” of the exposure- confounder - disease structure, confounding is precluded

50. 50 Randomization to Reduce Confounding  Definition: random assignment of subjects to exposure (or treatment) categories  All subjects  Randomize  One of the most important inventions of the 20th Century! Exposed Unexposed

51. 51 Randomization to Reduce Confounding D D

52. 52 Randomization to Reduce Confounding  All subjects  Randomize  Applicable only for intervention (experimental) studies  Special strength of randomization is its ability to control the effect of confounding variables about which the investigator is unaware  Does not, however, eliminate confounding! Exposed Unexposed