“Iron” Mike Webster was one of the greatest health outcome. It may also be admitted to prove centers to ever play professional football. Known the safety and efficacy of a product, to explain a for playing sleeveless in freezing temperatures defendant’s actions, or as the basis for an expert’s to intimidate his opponents, Webster spent 17 opinion. Given their general nature and inherent seasons in the NFL and helped lead the Pittsburg bias, epidemiological studies alone do not answer Steelers to four Super Bowl Championships in the questions of specific causation, i.e. whether an 1970’s. He was later inducted into the Pro Football agent caused a particular individual’s disease or Hall of Fame and named to the NFL’s all-time health outcome.7 team—a true football legend.1 CATEGORIES OF EPIDEMIOLOGIC STUDIES But the glory of football quickly faded after his There are two categories of epidemiologic retirement. Unable to keep a job and losing his studies: experimental and observational. In an marriage, Webster became homeless, depressed, experimental study, a researcher selects two indebted, drug-addicted, and plagued by chronic groups of individuals from a given population. pain that made sleep almost impossible. At one He then exposes one group to a suspected agent point Webster became so desperate for rest that while leaving the second group unexposed. he would shoot himself in the leg with a Taser until The researcher later evaluates both groups for he lost consciousness. In 2002, Mike Webster died development of the disease. of a heart attack at age 50.2 Experimental studies include randomized controlled What happened next would change professional trials and are often double-blinded, making them football forever. During Webster’s autopsy, forensic the “gold standard” of epidemiological evidence. pathologist and medical examiner Dr. Bennet However, experimental studies in humans are Omalu discovered that Webster suffered from ethically prohibited when an agent is known to be Chronic Traumatic Encephalopathy (CTE)—a brain potentially harmful. As a result, most epidemiologic disease never before seen in professional football studies are observational. players.3 In 2005, Omalu published his findings There are two main types of observational studies: in the medical journal Neurosurgery. CTE was cohort and case-control. Both types of studies catapulted into the national spotlight. But was have a comparison group and determine if there is football really the cause of Mike Webster’s rare an association between exposure to an agent and brain disease? The answer to that question is an a disease. If an association is present, the study epidemiological one. then measures the strength of that association. EPIDEMIOLOGY DEFINED In a cohort study, a researcher selects a group of “Epidemiology is the field of public health and individuals who have been exposed to the agent in medicine that studies the incidence, distribution, question and a second group who have not been and etiology of disease in human populations.”4 exposed. The researcher then follows the groups Epidemiology attempts to understand the cause and compares their development of the disease.8 and prevention of disease5 and is considered Behind randomized controlled trials, cohort studies among “the best evidence of causation in the mass are the strongest form of scientific evidence.9 torts context.”6 In contrast, case-control studies begin by Epidemiological evidence is often tendered as identifying a group of individuals who actually evidence of general causation, i.e. whether an have the disease and a second group who do not. agent is capable of causing a particular disease or The researcher then compares the groups’ past 11 12 exposures to the agent in question. If the agent positive association could result from random tells researchers that they can be 95% sure that not based on the random selection of patients. causes the disease, the researcher should find a error even if no association were in fact present.”19 the true relative risk is somewhere between Rather, researchers gain access to brains through higher proportion of past exposures among those For example, a p-value of 0.05—which is the most 2.14 and 3.36. The more narrow the confidence donations from families or by direction of the who have the disease.10 Case-control studies common significance level—means that there is a interval, the more precise the result. However, if the players themselves before their deaths. Because fall just below cohort studies in the hierarchy of 5% chance that the study will erroneously find an confidence interval includes 1.0, the result cannot the families of players who exhibited CTE-like scientific evidence.11 association where no true association exists. Thus, be “statistically significant.”20 symptoms during their lives are more likely to the researcher can be 95% sure that the observed donate a brain for research, the sample of brains Case reports, like the one regarding Mike Webster, 2. BIAS association is true. As long as the observed received is not representative. describe clinical events in a single patient and are The overarching objection to the existing body p-value for the study falls below the preselected among the weakest forms of scientific evidence.12 of CTE research is that it is based on inherently Even Dr. Ann McKee, director of Boston significance level, then the relative risk or odds Alone, case reports cannot establish a causal biased case reports. Bias refers to anything University’s CTE center and now the leading ratio can potentially be “statistically significant.” link between an agent and a disease primarily “that results in a systematic (nonrandom) error neuropathologist in the study of the disease, because there is no comparison group, and they A second way to assess random error is by using in a study result and thereby compromises its admits that “an autopsy series is terribly biased” are generally excluded at trial.13 Even Dr. Omalu a confidence interval. A confidence interval is validity.”21 There are two primary types of bias and by itself is unable to detect incidence and conceded that his case report of Mike Webster “by a range of values within which the true value is in epidemiological studies: selection bias and prevalence of the disease.23 In other words, case itself [could not] confirm a causal link between likely to fall. Suppose a study finds a relative risk information bias.22 reports cannot establish why or how frequently professional football and CTE.”14 (discussed below) of 2.66 with a 95% confidence the disease occurs in a given population. Selection bias results from the method by which interval of 2.14 to 3.36. The confidence interval PRESENCE OF ASSOCIATION study participants are chosen. CTE research is Information bias results from “inaccurate information However, Dr. Omalu’s diagnosis of CTE in Mike about either the disease or the exposure status of Webster was just the beginning. In November the study participants or a result of confounding.”24 2006, Omalu published a second case report15 after Because concussions in football are underreported finding CTE in the brain of former NFL player Terry and largely undocumented, it is difficult to Long, a 45-year-old former Pittsburg Steeler who reconstruct accurately a player’s medical history. As committed suicide in 2005 by drinking antifreeze.16 a result, researchers must often rely on interviews He later found evidence of CTE in the brains of with family members about the player’s exposures retired NFL players Justin Strzelczyk (age 36) which test memory and are speculative at best. and Andre Waters (age 44).17 Omalu’s research These interviews can also encourage “recall bias,” in appeared to show an association between playing which family members are more likely to report past professional football and CTE. But were these exposures once the disease has been confirmed. associations true, or merely the result of random error, bias, or confounding factors? ALONE, CASE REPORTS 1. RANDOM ERROR Epidemiologic studies are often based on CANNOT ESTABLISH A relatively small sample groups. As a result, a study CAUSAL LINK BETWEEN may erroneously find an association where one does not actually exist, or not find an association AN AGENT AND A DISEASE where one does exist, simply due to “chance” or PRIMARILY BECAUSE THERE “random error.”18 IS NO COMPARISON GROUP, One way to assess the potential for random error is by calculating a p-value. “A p-value AND THEY ARE GENERALLY represents the probability that an observed EXCLUDED AT TRIAL. 13 14 3. CONFOUNDING FACTORS by the incidence rate of disease in the unexposed association between the exposure and disease. Many jurisdictions will only admit epidemiologic A “confounding factor” is an “extra” factor in a group. A relative risk of 1.0 means that there is no A relative risk greater than 1.0 means there is a evidence if the relative risk is greater than 2.0—a study group which independently increases both association between an agent and a disease, and positive association between an agent and disease, level that permits an inference that the disease was the risk of disease and exposure.25 If not properly that the risk of contracting the disease is the same which could be causal. The higher the relative risk, more likely than not caused by the agent in question. accounted for, confounding factors can skew in both exposed and unexposed individuals. A the stronger the association. Others courts reject this reasoning and will admit the results of a study by producing an observed relative risk less than 1.0 means there is a negative epidemiologic studies with a relative of 2.0 or less as For example, suppose as a hypothetical that a association when no true association exists. evidence of causation, thereby leaving the sufficiency researcher wanted to test the safety of modern of the evidence to the jury to decide.32 Critics of Dr. Omalu’s work initially questioned A BASIC TENET OF football helmets compared to the leather whether the use of anabolic steroids was a EPIDEMIOLOGY IS THAT AN helmets worn by early players. After selecting ASSOCIATION VS. CAUSATION possible confounding factor because both Mike two equally-sized, equally-matched groups, the A basic tenet of epidemiology is that an Webster and Terry Long had used steroids during ASSOCIATION DOES NOT researcher would give leather helmets to one association does not equal causation. Rather, their football careers. After all, the known side group (exposed group) and modern helmets to the causation may only be inferred after a researcher effects of steroids include high blood pressure, EQUAL CAUSATION. other (unexposed group). Further suppose that at considers all known evidence in light of heart problems, aggression, psychiatric disorders, the end of the season, 66 out of 100 players with scientifically recognized guidelines. depression, and drug dependence—symptoms leather helmets sustained concussions, compared The Bradford Hill criteria provides a number of commonly displayed by NFL players later to only 22 out of 100 players with modern helmets. factors for researchers to consider in assessing diagnosed with CTE.26 To calculate the relative risk, the researcher would causation, including: (1) the existence of a temporal divide the incidence rate of concussion among While this theory has since been discredited relationship; (2) strength of the association; (3) players with leather helmets (66/100 = 0.66) by the through experimental testing on rats,27 and by dose-response relationship; (4) replication of the incidence rate of concussion among players with the discovery of CTE in players whose careers findings; (5) biological plausibility (coherence with modern helmets (22/100 = 0.22), equaling a relative predated the use of steroids in the NFL,28 other existing knowledge); (6) consideration of alternative risk 3.0 (0.66/0.22 = 3.0). This relative risk not potential confounding factors—like age, mental explanations; (7) cessation of exposure; (8) only shows a positive association between leather health, and substance abuse—have gone “largely specificity of the association; and (9) consistency helmets and concussions (because it is over 1.0), but unaccounted for in the published literature.”29 with other knowledge. While not all factors must also implies that players who wear leather helmets Without conducting experimental studies that be present for a causal relationship to exist, an are three times more likely to sustain a concussion.31 properly control for these factors, the link between assessment of causation requires this analysis.33 football and CTE remains suspect. For years the NFL has maintained that there is no STRENGTH OF ASSOCIATION scientific evidence directly linking CTE to football- Once a true association is determined related participation. Nonetheless, since 2002, almost (understanding that bias and chance can never 100 former NFL players have tested positive for be ruled out), a researcher can then evaluate the CTE, increasing health concerns among players and strength of that association. The strength of an leading to some early retirements. As the number of association refers to the “degree to which the risk players with CTE has continued to grow, so has the of disease increases when individuals are exposed chorus of media outlets insisting that football causes to an agent.”30 Epidemiologists commonly measure CTE and denigrating NFL administrators for failing the strength of an association in terms of relative to acknowledge the same. In March 2016, an NFL risk or odds ratio numbers. executive publically acknowledged for the first time a link between football and CTE.34 Relative risk, which is most commonly used in cohort studies, is calculated by dividing the Despite this acknowledgment, the science behind incidence rate of disease in the exposed group CTE is far from settled. After all, an association does

15 16 1. Frank Litsky, Mike Webster, 50, Dies, N.Y. TIMES (Sept. 25, 2002), http://www.nytimes. not equal causation. With only about 200 cases $100 million dollars to fund brain trauma research Practitioners should also consider holding a “Science com/2002/09/25/sports/mike-webster-50-dies-troubled-football-hall-of-famer. html?_r=0 of confirmed CTE across a variety of disciplines, and concussion awareness initiatives. Dr. Omalu’s Day” to educate the judge on epidemiology in cases 2. Greg Garber, A tormented soul, ESPN (Jan. 25, 2005), http://www.espn.com/nfl/news/ story?id=1972285 35 the study of the disease is still in its “infancy.” research was also the impetus for the NFL’s where such evidence plays a crucial role. “Science 3. Bennet I. Omalu et al., Chronic Traumatic Encephalopathy in a National Football League Player, 57 Neurosurgery 128-29 (2005). These limited results are further weakened by concussion injury litigation in which approximately Days” have been used in New Jersey and Illinois 4. Michael D. Green et al, Reference Guide on Epidemiology, in REFERENCE MANUAL ON SCIENTIFIC EVIDENCE 549, 551 (3d ed. 2011) (“Reference Guide on Epidemiology”). inherent selection bias in the CTE’s brain bank, 5,000 retired players sued the NFL for failing to courts to allow parties to explain the history and 5. Id. at 551. making it nearly impossible to extrapolate the warn them of the risks of concussions, resulting in background of products and to present relevant 6. In re Breast Implant Litig., 11 F. Supp. 2d 1217, 1224 (D. Colo. 1998). 7. Reference Guide on Epidemiology at 608-09. results to the general population. As stated by the an approved settlement of nearly $1 billion dollars.39 medical and scientific literature.40 Among other 8. Id. at 555-57. 9. Hassan Murad et al., New evidence pyramid, 0 Evidence Based Medicine 2 (2016), Third Circuit Court of Appeals, “[t]he NFL’s recent things, a well-executed “Science Day” lays the http://ebm.bmj.com/content/early/2016/06/23/ebmed-2016-110401.full Important and unanswered questions remain 10. Reference Guide on Epidemiology at 559. acknowledgment may very well advance the public groundwork for later motions to bar expert testimony 11. Murad, supra note 9, at 2. about the relationship between football and CTE. discussion of the risks of contact sports, but it did based on unreliable epidemiologic studies. 12. Id. 13. See, e.g., DeGidio v. Centocor Ortho Biotech, Inc., 3 F. Supp. 3d 674, 684 (N.D. Ohio 2014) Experimental studies of CTE in living subjects (noting the “widespread recognition among the federal courts that case reports alone 36 not advance the science.” cannot prove causation.”) (internal quotations omitted). need to be conducted, brain banks expanded, and 14. Omalu, supra note 3, at 132. 15. Bennet I. Omalu et al., Chronic Traumatic Encephalopathy in a National Football League What’s more, many of the leading CTE studies are advancements in player safety incorporated at all Player: Part II, 59 Neurosurgery 1086 (2006). 16. Lauren Ezell, Timeline: The NFL’s Concussion Crisis, PBS (Oct. 8, 2013), http://www.pbs. based on incomplete or unreliable information. In levels of the game. And at each step along the way, org/wgbh/pages/frontline/sports/league-of-denial/timeline-the-nfls-concussion-crisis/ 17. Id. two studies that collectively examined the brains with every study that is conducted, there to guide, 18. Reference Guide on Epidemiology at 572-73. of 93 former athletes, researchers were able to interpret, and help researchers better understand 19. Id. at 576. 20. Id. at 576-581. reconstruct the medical histories of only about half America’s favorite sport, will be epidemiology. 21. Id. at 583. 22. Id. of the subjects, and those were taken second hand 23. Interview by Michael Kirk with Ann McKee, Director of Neuropathology, Dep’t of Veterans DRUG & DEVICE APPLICATION Affairs, Bedford, Mass. (May 20, 2013) http://www.pbs.org/wgbh/pages/frontline/sports/ from family members. Moreover, virtually none league-of-denial/the-frontline-interview-ann-mckee/ A discussion of CTE and professional football 24. Reference Guide on Epidemiology at 585. of the published literature on CTE accounts for 25. Id. at 591. may seem a world apart from pharmaceutical and 37 26. Mayo Clinic Staff, Performance-enhancing drugs: Know the risks, Mayo Clinic (Oct. potential confounding factors. 15, 2015), http://www.mayoclinic.org/healthy-lifestyle/fitness/in-depth/performance- medical device litigation. However, the underlying enhancing-drugs/art-20046134 27. James D. Mills et al., Anabolic Steroids and Head Injury, 70 Neurosurgery 205, 209 (2012). Some studies have even failed to confirm the scientific principles and methods to support or 28. Boston University CTE Center, Member of NFL Hall of Fame Diagnosed with Degenerative Brain Disease (Oct. 29, 2009), http://www.bu.edu/cte/news/press-releases/ presence of CTE under expected circumstances. attack epidemiologic evidence are the same in october-28-2009/ 29. In re Nat. Football League Players’ Concussion Injury Litig., 307 F.R.D. 351, 399 (E.D. Pa. In a 2013 study of six retired football players from both contexts. So the next time you are presented 2015), aff’d sub nom. In re Nat’l Football League Players Concussion Injury Litig., 821 F.3d 410 (3d Cir. 2016), as amended (May 2, 2016) (internal citation omitted). the Canadian Football League, all six players had with epidemiological evidence, remember this 30. Reference Guide on Epidemiology at 566. 31. Interestingly, some researchers believe that wearing leather helmets—or wearing no helmets at all—might actually decrease the number of head injuries among football a history of repeated concussions and progressive discussion on CTE and ask: players. They theorize that the increased safety of modern helmets emboldens players to hit with greater speed and violence and causes them to use the helmet itself as a neurocognitive decline prior to their deaths, but weapon. If the hard plastic helmets were removed, the players would alter their tackling 1. Was the type of study appropriate to the research habits, thereby reducing head injuries. only three of the men had neuropathological 32. Id. at 566-67, 612, 616. question? 33. Id. at 552, 598-600. findings consistent with CTE. The study concluded 34. Bill Chappell, In a First, NFL Executive Admits Football is Linked to Brain Damage, NPR 2. Was an appropriate sample size used? (Mar. 15, 2016), http://www.npr.org/sections/thetwo-way/2016/03/15/470513922/in-a- that “it is difficult to establish a definitive link first-nfl-executive-admits-football-is-linked-to-brain-damage 3. How were the participants/controls recruited? 35. In re Nat. Football League Players’ Concussion Injury Litig., 307 F.R.D. at 398. between a history of multiple concussions and 36. See In re Nat’l Football League Players Concussion Injury Litig., 821 F.3d 410, 443 (3d Cir. 2016), as amended (May 2, 2016). 38 4. Were confounding factors considered and CTE” and that further research is required. 37. In re Nat. Football League Players’ Concussion Injury Litig., 307 F.R.D. at 398-99. appropriately accounted for? 38. Lili-Naz Hazrati et al., Absence of chronic traumatic encephalopathy in retired football players with multiple concussions and neurological symptomatology, 7 Frontiers in CONCLUSION Human Neuroscience 1 (2013). 5. How strong is the association between exposure and 39. See In re Nat’l Football League Players Concussion Injury Litig., 821 F.3d at 447. Dr. Omalu’s discovery of CTE has forever changed disease? 40. See, e.g., In re Depakote, No. 14-CV-847-NJR-SCW, 2015 WL 4775868, at *3 n.2 (S.D. Ill. Feb. 13, 2015). professional football. Since 2002, the NFL has 6. How wide is the confidence interval? revised return-to-play guidelines, altered kick- 7. Does the relative risk meet the jurisdictional off rules in hopes of reducing collision speeds, requirement for admissibility? instituted new concussion safety measures 8. Is the association consistent with other research or requiring that an independent neurologist be on scientific literature? the sidelines for every NFL game, banned “crown 9. How many Bradford Hill criteria are satisfied? of the helmet” hits outside of the tackle box (the 10. Do the numbers suggest causation? length of the offensive line), and donated over JOSH A. CHAD R. HILL HUTCHINSON 17 18