1. Alternatives and Enhancements to Intention to Treat Analyses of Randomized Trials Thomas B. Newman, MD, MPH February 20, 2002

2. Context Topic has interested me since draft lottery study Recent renewed interest in context of Appendix 12-B of Designing Clinical Research, 2nd edition PROBIT study provides a nice example Possibility of instrumental variables analysis of KPMCP phototherapy data

3. Example 1: Delayed Effects of the Military Draft on Mortality: 1 Origin of study: Agent Orange concern Design: “Randomized natural experiment”using the draft lottery Data source: computerized death certificate registries, CA and PA Predictor variable of interest: military service

4. Delayed Effects of the Military Draft on Mortality: 2 Predictor variable measured: date of birth, leading to a draft lottery number below that year’s cutoff

5. BUT: Having an eligible number was a poor measure of military service: For consistency with later examples, consider those randomized to be eligible in the Intervention group, and those exempt in the Control group

6. Algebraic Correction: Assume observed death rates for “intervention” (Ri) and control (Rc) are weighted averages of rates among those serving (A) and not serving (B). (Weighted by proportion serving) R I = p 1 A + (1-p 1 )B R C = p 2 A + (1-p 2 )B p1 = proportion serving in “Intervention” (eligible) group p2 = proportion serving in “Control” (exempt) group

7. Algebraic correction 2: What we want to know is the relative risk for military service (A/B) What we have is the relative risk for draft eligibility ( R I /R C ) Then with algebra it can be shown that : A/B =1-R I /R C + 1 p 2 R I /R C -p 1

8. Results

9. Examples of Other Questions Hard to Address with ITT Analyses Health benefits of breastfeeding Health benefits of quitting smoking Any intervention in which group allocation is a poor measure of actual predictor variable of interest

10. Example 2: Promotion of Breastfeeding Intervention Trial (PROBIT)* Cluster-randomized trial at 31 sites in Belarus Subjects 17,046 term singleton infants >2500g initially breastfed Intervention: WHO/UNICEF Baby Friendly Hospital Initiative Outcomes: BF @ 3,6,9,12 months and allergic, gastrointestinal and respiratory disease F/U to 12 months on 16,491 (96.7%) *Kramer MS et al., JAMA 2001

11. PROBIT, cont’d RQ#1: Does a breastfeeding promotion program increase exclusive breastfeeding? – Predictor = Group assignment – Outcome = Exclusive breast feeding – ITT analysis is fine RQ#2: How much does exclusive breastfeeding reduce the risk of atopic eczema in the infant? (What is NNEBF*? ) – Predictor = Exclusive breast feeding – Outcome = Atopic eczema – ITT won’t work -- too much misclassification *Number Needed to Exclusively Breast Feed

12. Results Exclusive BF at 3 months 40% vs 5%* Eczema 3.3% vs 6.3%; OR = 0.55 (95% CI 0.31-.95 based on GLIMMIX) Question: if the risk difference and risk ratio in this study are 3% and 0.55, what can we say about the values for exclusive breast feeding (as opposed to treatment allocation)? *(Rounded)

13. Question: What is the true effect of breast feeding, undiluted by misclassification bias? That is, what would the risk ratio and risk difference for eczema have been if everyone in the intervention group and no one in the control group had exclusively breast fed? Might be relevant for helping a working mother make an informed decision about whether to breastfeed exclusively. (NNEBF)

14. Approach #1 Assume, as in draft lottery study – There is a rate of eczema for breast fed infants (A) and a different rate for bottle fed infants (B) – These rates are not dependent on group assignment Then if p1 and p2 are proportions breastfed in the intervention and control groups, the observed rates of eczema in the two groups, R i and R c are: R I = p 1 A + (1-p 1 )B R C = p 2 A + (1-p 2 )B

15. Approach #1, cont’d To obtain the risk difference, we first subtract the two equations: R I = p 1 A + (1-p 1 )B R C = p 2 A + (1-p 2 )B R C -R I =p 2 A -p 1 A + B- p 2 B-B+p 1 B R C -R I = p 1 (B-A) +p 2 (A-B) R C -R I = p 1 (B-A) -p 2 (B-A) B-A = (R C - R I )/(p 1 -p 2 ) So difference in risk of eczema for exclusive BF is: (6.3%-3.3%)/(40%-5%)= 8.6%

16. Approach #1, cont’d But is assumption that A & B are independent of group assignment reasonable? What if babies who are breast fed in response to the intervention have a different risk of eczema from babies who would have breastfed anyway? (A i  A c ) – E.g. if intervention emphasized that a benefit of breastfeeding is prevention of allergic disease, those breast feed in response to the intervention might be those most worried about allergic disease – The risk of eczema in breastfed babies whose mothers breast fed in order to prevent allergic disease might be higher than among those who would breast feed anyway

17. Problem: Breast fed infants are really of two types: – Babies who breast feed anyway – Babies who breast feed only in response to the intervention – Risk of eczema in these two groups might differ – Only the intervention group includes the second type of infants Therefore, our assumption of a single rate of eczema for breast fed babies in both groups (A i =A c ) is probably not valid.

18. Recall question posed was: What would the risk ratio and risk difference for eczema be if everyone in the intervention group and no one in the control group had exclusively breast fed? – Answer: can’t tell from this study – Reason: there’s a potential interaction between effect of intervention on breast feeding and effect of breast feeding on eczema. (Extreme example: the intervention is effective at increasing breastfeeding only in those mothers whose babies are at risk for eczema)

19. Three types of infants Those who would breast feed anyway; Eczema rate=A Those who breast feed only with the intervention; Eczema rate = B Those that formula feed anyway; Eczema rate = C

20. Solution Explicitly model all types of infants Change the question we are asking to one that can be answered by the data

21. We can estimate the proportions of the three types of infants in each group Intervention Control P1 P2 BF Anyway BF from int. only Bottle feed anyway P1 P2 BF Anyway BF from int. only Bottle feed anyway Breast feeding Reason: the groups were randomly assigned, so there is no reason to expect baseline differences in proportions of different types of infants

22. Predicted eczema rates: R i = p2*A i + (p1-p2)*B i + (1-p1)*C i R c = p2*A c + (p1-p2)*B c + (1-p1)*C c

23. New assumption Ai=Ac; Ci=Cc – Reason: We don’t expect a breastfeeding intervention to affect the risk of eczema except by altering breastfeeding. In A and C groups (by definition) the intervention has no effect on breast feeding. (Violated if intervention covers other topics, like when to introduce solid foods.)

24. Risk difference Predicted Eczema Rates then are: R i = p2*A + (p1-p2)*B i + (1-p1)*C R c = p2*A + (p1-p2)*B c + (1-p1)*C Risk difference for BF in response to intervention is then: R c -R i = (p1-p2)*(B c -B i ) B c -B i =R c -R i /(p1-p2) Note that the right side of this equation is exactly the same as before! The point is to be clear on what is being estimated.

25. What does Bc-Bi estimate? The expected difference in eczema rates due to breastfeeding for infants susceptible to the breast feeding intervention It is more relevant clinically than the “B-A.” It is analogous to the expected effect of a medication on those who take it, which is more relevant to patients than the expected effect of medication on those to whom it is prescribed (which is diluted by those who don’t take it)

26. Counseling the Undecided Mother For a mother who is undecided about exclusive breastfeeding, the difference in eczema rates B c -B i is arguably the most relevant quantity! Since this is 8.6%, we can say that NNEBF is about 12

27. What if I want a Risk Ratio, not a Risk Difference? Recall: Ri = p2*A + (p1-p2)*Bi + (1-p1)*C Rc = p2*A + (p1-p2)*Bc + (1-p1)*C Simply taking the quotient of these two and rearranging gives: Bi/Bc = (Ri -X)/(Rc-X) where X = p2*A +(1-p1)*C Note that both A and C are estimable from the data A = risk in control group that GETs the intervention. C = risk in intervention group that does NOT get intervention.

28. Uh Oh. Does this mean RR in draft lottery paper are wrong? Well, the numbers are probably OK, but the text isn’t quite right Instead of saying we estimated the RR for military service, we should said we estimated the RR for military service due to the draft lottery. That is, it is quite possible that the effects of serving in the military for those who volunteered are different from those who were drafted, and the study cannot address the former.

29. Limitations Like compliance with medication, breastfeeding is not a dichotomous variable. Exclusive breastfeeding may be dichotomous, but its benefits will depend on who is in the comparison group This is a model, and models are only as good as their assumptions In this case, the assumption that C i =C c may be unreasonable, if intervention also increased BF among the 60% not exclusively BF.

30. Summary and Implication Intention to treat analysis gives biased measures of treatment effect when there is substantial misclassification of exposure Measuring adherence to the intervention (or success of the intervention on an intermediate endpoint) allows estimates of clinically relevant quantities Implication: measuring adherence to intervention (and its predictors) is important in the design of clinical trials