Module 4 Overview Context

1. Module 4 Overview Context Content Area: Interpretation of Epidemiological Evidence Essential Question (Generic): Is the association causal? Essential Question (Drug Abuse Specific): Is an association with drug abuse causal? Enduring Epidemiological Understanding: Causation is only one explanation for finding an association between an exposure and a disease. Because observational studies are complicated by factors not controlled by the observer, other explanations must also be considered. Synopsis: In Module 4, students explore the rationale and methods of interpreting epidemiological studies. Students develop skills to assess possible explanations for an association found in a study, with consideration of explanations of causality, chance, confounding, reversed time order, and bias. Module 4 concludes with consideration of methods for weighing the overall evidence for an association. Lessons: Lesson 4-1: Introduction to Interpreting Associations Lesson 4-2: Causality Lesson 4-3: Chance Lesson 4-4: Bias Lesson 4-5: Confounding Lesson 4-6: Reverse Time Order Lesson 4-7: Weighing the Evidence

2. Module 4 - Interpretation of Epidemiological Evidence • Lesson 4-6 Weighing the Evidence • Content • Description of a legal case involving a stillbirth and a mother who had used cocaine • Consideration of the evidence for causality related to this case and of the role that public opinion can also play • Big Ideas • An association found in a single study or several studies with the same result should consider five possible explanations for an association, including causality, chance, bias, confounding, and reverse time order • A judgment of causality may be made by considering several aspects of the strength and quality of an entire body of scientific evidence about an association This project is supported by a Science Education Drug Abuse Partnership Award, Grant Number 1R24DA016357-01, from the National Institute on Drug Abuse, National Institutes of Health.

3. Where are we? Essential Questions Enduring Understandings

4. McKnight Case “Regina McKnight is a 26-year-old native of Horry County, South Carolina. She has an IQ that, prior to trial, was measured at 72, i.e., “below average / borderline deficiency,” and attended special education classes in high school. She was unable to obtain a permanent job thereafter. Until 1998, Petitioner lived with her mother, who helped her with day-to-day needs. In 1998, however, Petitioner’s mother was killed by a hit and run driver. Left without the support system on which she had relied, she quickly spiraled downward, becoming homeless, addicted to both cocaine and marijuana – and pregnant. Lacking access to an adequate substance abuse treatment program, she was unable to overcome her drug dependence. (http://www.drugpolicy.org/docUploads/Petition_for_a_Writ_of_Certiorari.pdf)

5. McKnight Case “On May 15, 1999, McKnight was transported, in labor, to Conway Hospital, where she delivered a stillborn girl. There had been no prior indication that the fetus was in distress, and it has never been suggested that McKnight intended to harm the fetus. On the contrary, the attending nurse testified at trial to having comforted McKnight, who was grief-stricken by the stillbirth. As is common with distraught parents, Petitioner asked to hold the stillborn baby and requested that photographs of the baby be taken. She told hospital staff of the name – “Mercedes” – that she had picked out for the baby. She asked to be given a “memory certificate” with the baby’s footprints and the bracelet that the baby had worn. She also asked to see the hospital’s chaplain. (http://www.drugpolicy.org/docUploads/Petition_for_a_Writ_of_Certiorari.pdf)

6. McKnight Case “Within minutes of the stillbirth, however, hospital staff assumed a second role. Following a carefully developed “protocol,” they obtained a urine sample from McKnight, for drug testing. After that screen indicated that cocaine was present, a nurse, following the protocol, obtained McKnight’s signature on a form entitled “Informed Consent for Drug Testing,” and collected a second sample for “forensic” testing, with positive results reported to the State Department of Social Services (“DSS”). (http://www.drugpolicy.org/docUploads/Petition_for_a_Writ_of_Certiorari.pdf)

7. McKnight Case “McKnight was arrested on October 7, 1999, and charged under a statute proscribing “homicide by child abuse,” S.C. Code § 16-3-85, which makes it a felony to “cause the death of a child under the age of eleven while committing child abuse or neglect,” if the death occurs “under circumstances manifesting an extreme indifference to human life.” The law provides for a prison sentence of twenty years to life. Id. § 16-3-85(C). (http://www.drugpolicy.org/docUploads/Petition_for_a_Writ_of_Certiorari.pdf)

8. Background How Drugs Cross the Placenta http://www.merck.com/mmhe/sec22/ch259/ch259a.html

9. Background Cocaine

10. Background Stillbirth

11. Background Regina McKnight

12. McKnight Case Regina McKnight Homicide by Child Abuse

13. Demonstrating Causality Beyond a Reasonable Doubt The burden of proof required by the prosecution in a criminal trial to obtain a guilty verdict.

14. Review - Associations Tied Related Associated Linked What do we mean when we say that there is anassociationbetween two things? Things that are associatedare linked in some way that makes themturn up together.

15. Interpreting Associations versus Judging Causality • Causal • Chance • Bias • Confounding • Reverse Time Order On a study by study basis, we try to interpret associations by looking at possible explanations for those associations As a body of scientific knowledge accumulates, we consider all the evidence that is available and try to judge whether the weight of the evidence is sufficient to demonstrate a causal association.

16. Weighing the Evidence and Judging Causation Sir Austin Bradford Hill “The Environment and Disease: Association or Causation?” Proceedings of the Royal Society of Medicine January 14, 1965 Relevance to the McKnight Case

17. Explaining Associations and Judging Causation Sir Austin Bradford Hill “The Environment and Disease: Association or Causation?” Proceedings of the Royal Society of Medicine January 14, 1965 Relevance to the McKnight Case

18. Explaining Associations and Judging Causation “In what circumstances can we pass from this observed association to a verdict of causation?”

19. Causation: Epidemiological Versus Legal View January 1994 - By Nancy A. Dreyer THE PROCESS of determining causation and, in fact, the ultimate need to determine causation is different in law and science. In law, the goal of fairness seems to be paramount. Decisions are required, no matter whether the true causes are known or understood. In contrast, scientists have been described as "practitioners of a discipline that seeks, but never finds, absolute truth" and as people who use a "variety of criteria to evaluate data in conditions that provide less than total certainty."(1) If lawyers and courts knew how epidemiologists look at causation and were aware of some of the methods used to provide scientific inferences, perhaps they would recognize the case for accepting the tentativeness of science and the scientific process. At a minimum, this knowledge would enhance their facility to make fair and equitable decisions. “An Epidemiological View of Causation: How it Deffers from the Legal” at http://www.pbs.org/wgbh/pages/frontline/implants/legal/ defensejournal2.html Extension: Ask students to read this slide or pass as a handout.

20. Explaining Associations and Judging Causation “Here then are nine different viewpoints from all of which we should study association before we cry causation.”

21. Explaining Associations and Judging Causation Does the evidence support a verdict of causation? • Strength • Consistency • Specificity • Temporality • Biological Gradient • Plausibility • Coherence • Experiment • Analogy

22. Explaining Associations and Judging Causation Does the evidence support a verdict of causation? • Strength What is the strength of the association between prenatal cocaine exposure and stillbirth? What is the strength of the association between the exposure and the outcome?

23. Explaining Associations and Judging Causation Does the evidence support a verdict of causation? 2. Consistency Has the association between prenatal cocaine exposure and stillbirth been found consistently by different researchers, in different places, using different study designs? Has the association between the exposure and the outcome been found consistently by different researchers, in different places, using different study designs?

24. Explaining Associations and Judging Causation Does the evidence support a verdict of causation? 3. Specificity Is prenatal cocaine exposure only associated with stillbirth or is it associated with other outcomes as well? Is the exposure only associated one outcome or is it associated with other outcomes as well?

25. Explaining Associations and Judging Causation Does the evidence support a verdict of causation? 4. Temporality Have studies established that prenatal cocaine exposure precedes the stillbirth? Have studies established that the exposure precedes the outcome?

26. Explaining Associations and Judging Causation Does the evidence support a verdict of causation? 5. Biological Gradient Has a biological gradient been demonstrated between prenatal cocaine exposure and stillbirth? Has a biological gradient been demonstrated between the exposure and the outcome?

27. Explaining Associations and Judging Causation Does the evidence support a verdict of causation? 6. Plausibility Is it biologically plausible that prenatal cocaine exposure could cause stillbirth? Is it biologically plausible that the exposure could cause the outcome?

28. Explaining Associations and Judging Causation Does the evidence support a verdict of causation? 7. Coherence Is the finding of an association between prenatal cocaine exposure and stillbirth coherent with our earlier knowledge? Is the finding of an association between the exposure and the outcome coherent with our earlier knowledge?

29. Explaining Associations and Judging Causation Does the evidence support a verdict of causation? 8. Experimental Is there experimental evidence, in which stillbirths have been produced by the prenatal administration of cocaine? Is there experimental evidence, in which the outcome have been produced by the administration of exposure?

30. Explaining Associations and Judging Causation Does the evidence support a verdict of causation? 9. Analogy Is the association between prenatal cocaine exposure and stillbirth analogous to another association between an exposure and an outcome ? Is the association between the exposure and the outcome analogous to another association between an exposure and an outcome ?

31. Back to the McKnight Case Appeal

32. Explaining Associations and Judging Causation Amicus Curiae Friend of the Court

33. Explaining Associations and Judging Causation Amicus Curiae Friend of the Court

34. Explaining Associations and Judging Causation Amicus Curiae Claim: Trial Counsel was ineffective for: • failing to conduct an independent investigation that would have revealed readily accessible scientific information, evidence, and potential experts who could have testified regarding the etiology of stillbirths, the state of scientific knowledge regarding prenatal exposure to cocaine, and the nature of addiction. • failing to effectively cross examine the state's experts, and to call witnesses that were favorable to the defendant; • failing to adequately challenge the State’s case for causation which was based largely on misinformation, myth and prejudice, rather than scientific fact. Friend of the Court

35. Explaining Associations and Judging Causation Assignment • Read the friend-of-the-court brief. • Identify the passages that address evidence for causality and the five possible explanations for an association. • Identify the passages that address the five possible explanations. • Categorize, according to Hill’s cause / effect questions, the scientific information, evidence, and expert testimony identified in the friends-of-the-court brief that they think are good arguments for: • A prosecution team trying to uphold the conviction • A defense team trying to reverse the verdict against Regina McKnight

36. END OF FIRST OF TWO CLASSES FOR Lesson 4.7

37. Important Statement / Caveat “It is important to note that each and every amicus curiae is committed to reducing potential drug-related harms at every reasonable opportunity. Thus, amici do not endorse the non-medical use of drugs – including alcohol or tobacco – during pregnancy, by either parent. Nor do amici contend that there are no health risks associated with cocaine (or other drug or alcohol) use during pregnancy. Nonetheless, it is entirely consistent with amici’s public health and ethical mandates to bring to this Court’s attention the medical and scientific information that is relevant to the case at hand.”

38. Main Argument: Importance of Science “… it is vital that convictions be based on valid scientific evidence rather than conjecture and misinformed popular opinion.”

39. Influence of Popular Opinion “For nearly two decades before trial, the popular press was suffused with highly prejudicial and often inaccurate information about the effects of in utero cocaine exposure.”

40. Science Versus Popular Opinion “… valid scientific evidence … (or) misinformed popular opinion.”

41. Science Versus Popular Opinion “… valid scientific evidence … (or) misinformed popular opinion.”

42. Influence of Circumstantial Evidence “… circumstantial case of guilt by simply producing evidence of a stillbirth, and the fact of cocaine use or any other unwise or unpopular behavior.”

43. Precautions During Pregnancy Avoid … • Ingesting caffeine • Gardening without gloves • Changing a cat litter box • Contact with anyone who is smoking • Inhaling when handling household cleaning products • Consuming unpasteurized cheese or undercooked meat

44. A Weight of Evidence Review in JAMA Deborah A. Frank et al., Growth, Development, and Behavior in Early Childhood Following Prenatal Cocaine Exposure: A Systematic Review, 285 JAMA 1613 (2001)

45. Three Criteria for Studies Included in JAMA Review Detailed review was … restricted to studies that … met three criteria: 1. samples were prospectively recruited;

46. Three Criteria for Studies Included in JAMA Review Detailed review was … restricted to studies that … met three criteria: 1. samples were prospectively recruited; 2. examiners of the children were masked to their cocaine exposure status;

47. Three Criteria for Studies Included in JAMA Review Detailed review was … restricted to studies that … met three criteria: 1. samples were prospectively recruited; 2. examiners of the children were masked to their cocaine exposure status; 3. the cocaine exposed cohort did not include a substantial proportion of children also exposed in utero to opiates, amphetamines, or phecyclidine, or whose mothers were known to be infected with the human immunodeficiency virus (HIV).”

48. Conclusions of 2001 JAMA Review Deborah A. Frank et al., Growth, Development, and Behavior in Early Childhood Following Prenatal Cocaine Exposure: A Systematic Review, 285 JAMA 1613 (2001)

49. Another Study Cited in the Brief A Addis, ME Moretti, FA Syed, TR Einarson, G Koren Fetal effects of cocaine: An updated meta-analysis, Reproductive Toxicology 2001; 15(4):341-369 What is a meta-analysis? A technique for combining information from a number of studies in order to come up with a summarization of the findings The authors of Fetal Effects analyzed “all studies employing methodologies suitable for proving cause and effect relationships between cocaine and adverse pregnancy outcomes.”

50. Exclusions to Increase Rigor of Analysis “Studies were excluded based on several criteria: because they were case reports, editorials, letters, reviews or commentaries, studies without fetal or pregnancy outcomes, in vitro studies or placenta profusion, studies with outcomes not within the scope of the meta-analysis, studies without a control group and studies where cocaine users had not been separated from users of other drugs.”