Case-Control Studies: An Example

1. Case-Control Studies:An Example EP 711 November 8, 2011

2. Issues in Study Design and Interpretation • Type of study • Case definition • Control definition • Sources of exposure information • Exposure definition • Potential confounders • Potential sources of bias

3. Louik C et al: N Engl J Med 2007;356:2675-83

4. Background • ≥10% of pregnant women experience depressive symptoms in pregnancy • Medications represent one treatment option • SSRIs first marketed in 1988 and gained widespread acceptance • RDD survey in 2005 indicated that among women aged 18-44, ~8% used an SSRI in the week preceding interview

5. Background • Advantages of SSRIs • Established efficacy • Favorable side effect profile • Serum monitoring not required • Toxicity/overdose not a major problem

6. Background • SSRIs include • Fluoxetine (Prozac) • Sertraline (Zoloft) • Paroxetine (Paxil) • Citalopram (Celexa) • Fluvoxamine (Luvox) • Escitalopram (Lexapro)

7. Background • Congenital malformations • Major defects affect about 2-3% of livebirths • Encompasses a wide variety of defects • Some are extremely rare, e.g. limb reduction defects (2-4/10,000) • Others are more common, e.g. cleft lip (1/700), neural tube defects (1/1000) • Heart defects occur about 1/200 births

8. Background • Initial studies • Small cohorts from pregnancy registries • Results reassuring with respect to birth defects overall

9. Background • Later studies • Larger • Found no increased risk for birth defects overall, but • Increased risk for some specific defects • 3 independent studies reported increased risk for heart defects

10. Objectives • Examine 1st trimester use of specific SSRIs in relation to specific birth defects • Test existing hypotheses • Craniosynostosis • Omphalocele • Heart defects • Explore other defects not yet reported • Focus on specificity to help reduce misclassification

12. Choice of Study Design • Birth defects occur in 2-3% of livebirths (not uncommon) • Short latent period (9 months) • So why not cohort??

13. Choice of Study Design • “Birth Defects” is NOT a single outcome, and individually, THEY ARE RARE • Major birth defects affect 2-3% of newborns • However, specific defects typically affect only ~2/1000 to 1/10,000 • Known teratogens typically increase the risk of a specific defect or a group of related defects (syndrome or sequence)

14. Choice of Study Design • Therefore, a case-control approach is better suited to our research question looking at specific defects.

15. Types of Case-Control Studies

16. Methods • Study subjects • Infants with any of a wide range of malformations (isolated minor defects excluded) • Sample of non-malformed infants from same birth hospitals

17. Methods • Identified in 5 study centers • Study staff review clinic/surgical logs, admission/discharge lists, contact newborn nursery and labor/delivery rooms • In 2 study centers, use statewide birth defects registries • Nonmalformed infants identified at study hospitals • In Mass., population-based random sample of newborns

18. Methods • Mothers interviewed within 6 months of birth • Trained study nurses • By telephone • Questions address • Demographics • Reproductive history • Medical history • Lifestyle habits • Detailed medication history (includes prescription, over-the-counter, and herbal products)

19. Case definition--Theory • Specific as possible • Strict criteria • Should be reasonable to think that they have a common etiology

20. Case Definition--Applied • Cases are infants with heart defects • Concerns • No rigorous definition • Not homogeneous • Solution • Blind review of all infants with a heart-related defect • Sub-classify into embryologically meaningful groups to increase homogeneity

21. Case Definition--Applied • Case subgroups • Looping, laterality, and single ventricle defects • Conotruncal defects • Atrioventricular canal defects • Right ventricular outflow tract obstruction defects • Left ventricular outflow tract obstruction defects • Septal defects • Anomalous pulmonary venous return

22. Normal Heart

23. Pulmonary Valve Stenosis

24. Ventricular Septal Defect

25. Control Definition--Theory • Sample of the population that produced the cases • Sampled independently of exposure status

26. Control Definition--Applied • Infants with other malformations • Advantages • From same population as cases • Should remember pregnancy events similarly to cases • Disadvantages • May not reflect exposure status in population that gave rise to cases, i.e. exposure may be associated with increased risk of these defects too

27. Control Definition--Applied • Nonmalformed infants • Advantages • From same population as cases • Should reflect exposure status in the population that gave rise to cases • Disadvantages • May remember pregnancy events differently than cases (recall bias)

28. Control Definition--Applied • We will use nonmalformed controls • Address disadvantages by • Asking focused exposure questions (evidence exists that this enhances recall) • Considering other antidepressants (recall bias, if present, should apply to these too)

29. Exposure Assessment--Theory • Need sufficient detail of nature, duration, and timing of exposure • Accuracy is critically important • Sources of Information • Biomarkers • Records • Interviews

30. Exposure Assessment--Applied • Biomarkers—not applicable • Records • Medical records • Multiple providers • Prescription ≠ Consumption • Complete? • Pharmacy • No OTC meds, herbals • Dispense ≠ Use

31. Exposure Assessment--Applied • Interview • Greater detail available • Potentially includes all drugs • Relies on mother’s recollection • Because we chose to use nonmalformed controls, may differ between cases and controls (recall bias)

32. Source of Selected Prescription Drugs 5,435 Mothers; Boston, Philadelphia, Toronto, Iowa, 1976-1984 Mitchell AA, Cottler LB, Shapiro S. Effect of questionnaire design on recall of drug exposure in pregnancy. Am J Epidemiol 1986;123:670‑6.

33. Exposure Assessment J Womens Health (Larchmt). 2008 Sep;17(7):1073-80. Prescription medication borrowing and sharing among women of reproductive age. Petersen EE, Rasmussen SA, Daniel KL, Yazdy MM, Honein MA. National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA. 33

34. Exposure Assessment Overall, 28.8% of women and 26.5% of men reported ever borrowing or sharing prescription medications. Women of reproductive age were more likely to report prescription medication borrowing or sharing (36.5%) than women of nonreproductive age (>or=45 years) (19.5%) 34

35. A quarter of new prescriptions go unfilled, study finds February 18, 2010 35

36. Exposure Assessment More than a quarter of new prescriptions are unfilled, especially when the drugs are for symptomless conditions, researchers from Boston's Brigham and Women's Hospital have found. Physicians have long been concerned that many patients fill new prescriptions one time, then never get refills. But it has been impossible in the past to determine adherence to new prescriptions. The new study was made possible by the implementation of an electronic-prescribing initiative by two Massachusetts health plans. 36

37. Exposure Assessment—Evidence of Completeness* • False negatives • Valium reports—1975 • Medical records—1.2% • Maternal interview—5.8% • 20% from sources other than physician • Bendectin—late 1970’s, used exclusively in pregnancy • Manufacturer’s data—25% • Interview data—24% *Mitchell AA, Cottler LB, Shapiro S. Effect of questionnaire design on recall of drug exposure in pregnancy. Am J Epidemiol 1986;123:670‑6.

38. Exposure Assessment—Evidence of Completeness* • False positives • Elamar *Mitchell AA, Cottler LB, Shapiro S. Effect of questionnaire design on recall of drug exposure in pregnancy. Am J Epidemiol 1986;123:670‑6.

39. Exposure Assessment—Addressing Recall Bias • If recall is complete, recall bias cannot exist • Enhancement of recall will diminish recall bias

40. Reported Drug Use by Question Asked532 Women; Boston - 1975, and Toronto - 1978

41. Exposure Assessment • Series of questions about medications used any time from 2 months prior to LMP through the pregnancy • Illnesses they may have had, and medications used

42. Exposure Assessment • List of indications for which medications might be used • Anxiety, depression, other psychological conditions • Use of specific medications • Prozac, Zoloft, Paxil, Effexor, Elavil, Celexa, Luvox, Lexapro, Wellbutrin

43. Exposure Assessment—Details • Timing • First trimester • 28 days prior to LMP through the 4th lunar month • Nature • Any SSRI • Specific SSRI • Non-SSRI antidepressants • Helps assess presence of recall bias • Helps assess “confounding by indication”

44. Exposure Assessment • Referent group • Women who reported no exposure to any antidepressant at any time (56 days prior to LMP through the pregnancy) • Exclusions • Women whose only exposure was either 28-56 days prior to LMP or after the 4th lunar month

45. Potential confounders • Factors related to exposure and to outcome that explain results • Maternal age Parity • Maternal race/ethnicity History of seizures, diabetes, hypertension • Maternal education Infertility • Smoking history Folic acid use • Alcohol consumption LMP year • Family history of birth defects Study center • BMI

46. Results • 5,860 nonmalformed infants • Rate of exposure to any SSRI in controls—2.8%

47. Results • 3,724 infants with congenital heart defects (100 exposed) • 186 looping, laterality defects (2 exposed) • 620 conotruncal defects (13 exposed) • 164 atrioventricular defects (0 exposed) • 363 RVOTO (15 exposed) • 482 LVOTO defects (15 exposed) • 1161 septal defects (32 exposed) • 17 anomalous pulmonary venous return (0 exposed)

48. All cardiac defects

49. Results • Create more homogeneous classes • Specific cardiac defects • Septal defects • RVOTO defects • Specific SSRIs • Fluoxetine • Sertraline • Paroxetine

50. Septal defects