Below, I have collected some of the case law and commentary on the issue of using relative and attributable risks to satisfy plaintiff’s burden of showing, more likely than not, that an exposure or condition caused his or her disease or injury.

Johnston v. United States, 597 F. Supp. 374, 412, 425-26 (D. Kan. 1984)

Allen v. United States, 588 F. Supp. 247 (1984), rev’d on other grounds, 816 F.2d 1417 (10^th Cir. 1987)

In re TMI Litig., 193 F.3d 613, 629 (3d Cir. 1999)(rejecting “doubling dose” trial court’s analysis), amended, 199 F.3d 158 (3d Cir. 2000)

In re Hanford Nuclear Reservation Litig., 1998 WL 775340, at *8 (E.D.Wash. Aug. 21, 1998), rev’d, 292 F.3d 1124, 1136-37 (9^th Cir. 2002)

Cook v. United States, 545 F. Supp. 306, 308 (N.D. Cal. 1982)(“Whenever the relative risk to vaccinated persons is greater than two times the risk to unvaccinated persons, there is a greater than 50% chance that a given GBS case among vaccinees of that latency period is attributable to vaccination, thus sustaining plaintiff’s burden of proof on causation.”)

Padgett v. United States, 553 F. Supp. 794, 800 – 01 (W.D. Tex. 1982) (“From the relative risk, we can calculate the probability that a given case of GBS was caused by vaccination. . . . [A] relative risk of 2 or greater would indicate that it was more likely than not that vaccination caused a case of GBS.”);

Manko v. United States, 636 F. Supp. 1419, 1434 (W.D. Mo. 1986)(relative risk of 2, or less, means exposure not the probable cause of disease claimed), aff’d in relevant part, 830 F.2d 831 (8^th Cir. 1987)

Marder v. G.D. Searle & Co., 630 F. Supp. 1087, 1092 (D.Md. 1986) (“In epidemiological terms, a two-fold increased risk is an important showing for plaintiffs to make because it is the equivalent of the required legal burden of proof—a showing of causation by the preponderance of the evidence or, in other words, a probability of greater than 50%.”), aff’d mem. on other grounds sub nom. Wheelahan v. G.D.Searle & Co., 814 F.2d 655 (4^th Cir. 1987)(per curiam)

Lynch v. Merrill-National Laboratories, 646 F.Supp. 856 (D. Mass. 1986)(granting summary judgment), aff’d, 830 F.2d 1190, 1197 (1^st Cir. 1987)(distinguishing between chances that “somewhat favor” plaintiff and plaintiff’s burden of showing specific causation by “preponderant evidence”)

DeLuca v. Merrell Dow Pharm., Inc., 911 F.2d 941, 958-9 (3d Cir. 1990)

Daubert v. Merrell Dow Pharms., Inc., 43 F.3d 1311, 1321 (9th Cir.)(“Daubert II”)(holding that for epidemiological testimony to be admissible to prove specific causation, there must have been a relative risk for the plaintiff of greater than 2) (“For an epidemiological study to show causation under a preponderance standard . . . the study must how that children whose mothers took Bendectin are more than twice as likely to develop limb reduction birth defects as children whose mothers did not.”), cert. denied, 516 U.S. 869 (1995)

DePyper v. Navarro, 1995 WL 788828 (Mich. Cir. Ct. Nov. 27, 1995)

Oxendine v. Merrell Dow Pharm., Inc., 1996 WL 680992 (D.C. Super. Ct. Oct. 24, 1996)

Merrell Dow Pharms., Inc. v. Havner, 953 S.W.2d 706, 716 (Tex. 1997) (holding, in accord with the weight of judicial authority, “that the requirement of a more than 50% probability means that epidemiological evidence must show that the risk of an injury or condition in the exposed population was more than double the risk in the unexposed or control population”); id. at at 719 (rejecting isolated statistically significant associations when not consistently found among studies)

Hall v. Baxter Healthcare, 947 F.Supp. 1387, 1392, 1397, 1403-04 (D. Ore. 1996)(discussing relative risk of 2.0)

Pick v. American Medical Systems, Inc., 958 F. Supp. 1151, 1160 (E.D.La. 1997) (noting, in penile implant case, that “any” increased risk suggests that the exposure “may” have played some causal role)

In re Breast Implant Litigation, 11 F. Supp. 2d 1217, 1226 -27 (D. Colo. 1998)(relative risk of 2.0 or less shows that the background risk is at least as likely to have given rise to the alleged injury)

Barrow v. Bristol-Myers Squibb Co., 1998 WL 812318 (M.D. Fla. Oct. 29, 1998)

Allison v. McGhan Med. Corp., 184 F.3d 1300, 1315n.16, 1316 (11^th Cir. 1999)(affirming exclusion of expert testimony based upon a study with a risk ratio of 1.24; noting that statistically significant epidemiological study reporting an increased risk of marker of disease of 1.24 times in patients with breast implants was so close to 1.0 that it “was not worth serious consideration for proving causation”; threshold for concluding that an agent more likely than not caused a disease is 2.0, citing Federal Judicial Center, Reference Manual on Scientific Evidence 168-69 (1994))

Grant v. Bristol-Myers Squibb, 97 F. Supp. 2d 986, 992 (D. Ariz. 2000)

Pozefsky v. Baxter Healthcare Corp., No. 92-CV-0314, 2001 WL 967608, at *3 (N.D.N.Y. August 16, 2001) (excluding causation opinion testimony given contrary epidemiologic studies; noting that sufficient epidemiologic evidence requires relative risk greater than two)

In re Silicone Gel Breast Implant Litig., 318 F. Supp. 2d 879, 893 (C.D. Cal. 2004)

Norris v. Baxter Healthcare Corp., 397 F.3d 878 (10th Cir. 2005) (discussing but not deciding specific causation and the need for relative risk greater than two; no reliable showing of general causation)

Barrow v. Bristol-Meyers Squibb Co., 1998 WL 812318, at *23 (M.D. Fla., Oct. 29, 1998)

Minnesota Mining and Manufacturing v. Atterbury, 978 S.W.2d 183, 198 (Tex.App. – Texarkana 1998) (noting that “[t]here is no requirement in a toxic tort case that a party must have reliable evidence of a relative risk of 2.0 or greater”)

Washington v. Armstrong World Indus., Inc., 839 F.2d 1121 (5^th Cir. 1988)(affirming grant of summary judgment on grounds that there was insufficient evidence that plaintiff’s colon cancer was caused by asbestos)

Lee v. Johns Manville Corp., slip op. at 3, Phila. Cty. Ct. C.P., Sept. Term 1978, No. 88 (123) (Oct. 26, 1983) (Forer, J.)(entering verdict in favor of defendants on grounds that plaintiff had failed to show that his colo rectal cancer had been caused by asbestos exposure after adducing evidence of a relative risk less than two)

Primavera v. Celotex Corp., Phila. Cty. Ct. C.P., December Term, 1981, No. 1283 (Bench Op. of Hon. Berel Caesar, (Nov. 2, 1988) (granting compulsory nonsuit on the plaintiff’s claim that his colorectal cancer was caused by his occupational exposure to asbestos)

Grassis v. Johns-Manville Corp., 248 N.J.Super. 446, 455-56, 591 A.2d 671, 676 (App. Div. 1991)

Landrigan v. Celotex Corp., 127 N.J. 404, 419, 605 A.2d 1079 (1992)

Caterinicchio v. Pittsburgh Corning Corp., 127 N.J. 428, 605 A.2d 1092 (1992)

In re Joint E. & S. Dist. Asbestos Litig., 758 F. Supp. 199 (S.D.N.Y. 1991), rev’d sub nom. Maiorano v. Owens Corning Corp., 964 F.2d 92 (2d Cir. 1992)

Maiorana v. National Gypsum, 827 F. Supp. 1014, 1043 (S.D.N.Y. 1993), aff’d in part and rev’d in part, 52 F.3d 1122, 1134 (2d Cir. 1995)

Jones v. Owens-Corning Fiberglas Corp., 288 N.J. Super. 258, 266, 672 A.2d 230, 235 (App. Div. 1996)

Keene Corp. v. Hall, 626 A.2d 997 (Md. Spec. Ct. App. 1993)(laryngeal cancer)

In re W.R. Grace & Co., 355 B.R. 462, 483 (Bankr. D. Del. 2006) (requiring showing of relative risk greater than two to support property damage claims based on unreasonable risks from asbestos insulation products).

Ambrosini v. Upjohn, 1995 WL 637650, at *4 (D.D.C. 1995)

Ambrosini v. Labarraque, 101 F.3d 129, 135 (D.C. Cir. 1996)(Depo-Provera, birth defects)

Miller v. Pfizer, 196 F. Supp. 2d 1062, 1079 (D. Kan. 2002) (acknowledging that most courts require a showing of RR > 2, but questioning their reasoning), aff’d, 356 F. 3d 1326 (10th Cir. 2004)

Smith v. Wyeth-Ayerst Laboratories Co., appears to recognize that risk and cause are distinct concepts. 278 F. Supp. 2d 684, 691 (W.D.N.C. 2003) (“Epidemiologic data that shows a risk cannot support an inference of cause unless (1) the data are statistically significant according to scientific standards used for evaluating such associations; (2) the relative risk is sufficiently strong to support an inference of ‘more likely than not’; and (3)  the epidemiologic data fits the plaintiff’s case in terms of exposure, latency, and other relevant variables.”)

Burton v. Wyeth-Ayherst Laboratories, 513 F. Supp. 2d 719 (N.D. Tex. 2007)

In re Bextra and Celebrex Marketing Sales Practices and Prod. Liab. Litig., 524 F. Supp. 2d 1166, 1172 (N.D. Calif. 2007)(observing that epidemiologic studies “can also be probative of specific causation, but only if the relative risk is greater than 2.0, that is, the product more than doubles the risk of getting the disease”)

In re Viagra Products Liab. Litigat., 572 F. Supp. 2d 1071, 1078 (D. Minn. 2008)(noting that some but not all courts have concluded relative risks under two support finding expert witness’s opinion to be inadmissible).

In re Agent Orange Product Liab. Litig., 597 F. Supp. 740, 785, 836 (E.D.N.Y. 1984) (“A government administrative agency may regulate or prohibit the use of toxic substances through rulemaking, despite a very low probability of any causal relationship.  A court, in contrast, must observe the tort law requirement that a plaintiff establish a probability of more than 50% that the defendant’s action injured him. … This means that at least a two-fold increase in incidence of the disease attributable to Agent Orange exposure is required to permit recovery if epidemiological studies alone are relied upon.”), aff’d 818 F.2d 145, 150-51 (2d Cir. 1987)(approving district court’s analysis), cert. denied sub nom. Pinkney v. Dow Chemical Co., 487 U.S. 1234 (1988)

Sanderson v. Int’l Flavors & Fragrances, Inc., 950 F. Supp. 981, 998 n. 17,  999-1000, 1004 (C.D.Cal.1996) (more than a doubling of risk is required in case involving aldehyde exposure and claimed multiple chemical sensitivities)

Wright v. Willamette Indus., Inc., 91 F.3d 1105 (8th Cir. 1996)(“Actions in tort for damages focus on the question of whether to transfer money from one individual to another, and under common-law principles (like the ones that Arkansas law recognizes) that transfer can take place only if one individual proves, among other things, that it is more likely than not that another individual has caused him or her harm.  It is therefore not enough for a plaintiff to show that a certain chemical agent sometimes causes the kind of harm that he or she is complaining of.  At a minimum, we think that there must be evidence from which the factfinder can conclude that the plaintiff was exposed to levels of that agent that are known to cause the kind of harm that the plaintiff claims to have suffered. See Abuan v. General Elec. Co., 3 F.3d at 333.  We do not require a mathematically precise table equating levels of exposure with levels of harm, but there must be evidence from which a reasonable person could conclude that a defendant’s emission has probably caused a particular plaintiff the kind of harm of which he or she complains before there can be a recovery.”)

McDaniel v. CSX Transp., Inc., 955 S.W.2d 257, 264 (1997) (doubling of risk is relevant but not required as a matter of law)

Lofgren v. Motorola, 1998 WL 299925 *14 (Ariz. Super. 1998) (TCE, cancer)

Berry v. CSX Transp., Inc., 709 So. 2d 552 (Fla. D. Ct.App. 1998)(solvents, toxic encephalopathy)

Bartley v. Euclid, Inc., 158 F.3d 261 (5^th Cir. 1998)

Magistrini v. One Hour Martinizing Dry Cleaning, 180 F. Supp. 2d 584, 591-92 (D.N.J.2002) (‘‘the threshold for concluding that an agent was more likely than not the cause of an individual’s disease is a relative risk greater than 2.0’’), aff’d, 68 F. App’x 356 (3d Cir. 2003)

Ferguson v. Riverside School Dist. No. 416, 2002 WL 34355958 (E.D. Wash. Feb. 6, 2002)(No. CS-00-0097-FVS)

Daniels v. Lyondell-Citgo Refining Co., 99 S.W.3d 722, 727 (Tex. App. – Houston [1^st Dist.] 2003)

Graham v Lautrec Ltd., 2003 WL 23512133 (Mich. Cir. Ct., July 24, 2003)

Theofanis v. Sarrafi, 791 N.E.2d 38,48 (Ill. App. 2003)(reversing and granting new trial to plaintiff who received an award of no damages when experts testified that relative risk was between 2.0 and 3.0)(“where the risk with the negligent act is at least twice as great as the risk in the absence of negligence, the evidence supports a finding that, more likely than not, the negligence in fact caused the harm”).

Cano v. Everest Minerals Corp., 362 F. Supp. 2d 814, 846 (W.D. Tex. 2005)(relative risk less than 3.0 represents only a weak association)

Mobil Oil Corp. v. Bailey, 187 S.W.3d 263, 268 (Tex. App. – Beaumont 2006)

Cook v. Rockwell Internat’l Corp., 580 F. Supp. 2d 1071, 1088-89 (D. Colo. 2006)

In re Lockheed Litig. Cases, 115 Cal. App. 4th 558 (2004), rev’d in part, 23 Cal. Rptr. 3d 762, 765 (Cal. App. 2d Dist. 2005), cert. dismissed, 192 P.3d 403 (Cal. 2007)

Watts v. Radiator Specialty Co., 990 So. 2d 143 (Miss. 2008)(“The threshold for concluding that an agent was more likely than not the cause of an individual’s disease is a relative risk greater than 2.0.”)

Henricksen v. Conocophillips Co., 605 F. Supp. 2d 1142, 1158 (E.D. Wash. 2009) (noting that under Circuit precedent, epidemiologic studies showing low-level risk may suffiicent to show general causation but are sufficient to show specific causation only if relative risk exceeds two) (excluding plaintiff‘s expert witness’s testimony because epidemiologic evidence iis “contradictory and inconsistent”)

George v. Vermont League of Cities and Towns, 2010 Vt. 1, 993 A.2d 367, 375 (2010)

City of San Antonio v. Pollock, 284 S.W.3d 809, 818 (Tex. 2009) (holding testimony admitted insufficient as matter of law).

Michael Dore, “A Commentary of the Use of Epidemiological Evidence in Demonstrating Cause-in-Fact,” 7 Harv. Envt’l L.Rev. 429, 431-40 (1983)

Bert Black & David E. Lilienfeld, Epidemiologic Proof in Toxic Tort Litigation, 52 Fordham L. Rev. 732, 767 – 69 (1984)

David E. Lilienfeld & Bert Black, “The Epidemiologist in Court,” 123 Am. J. Epidemiology 961, 963 (1986)(a relative risk of 1.5 allows an inference of attributable risk of 33%, which means any individual case is less likely than not to be causally related)

Powell, “How to Tell the Truth With Statistics: A New Statistical Approach to Analyzing the Bendectin Epidemiological Data in the Aftermath of Daubert v. Merrell Dow Pharmaceuticals,” 31 Houston L. Rev. 1241, 1310 (1994) (“The plaintiff who wishes to reach the jury on the issue of causation must submit a statistical analysis indicating that exposure to the drug in question more likely than not caused the birth defects in question.  To support a finding of causation, the meta-analysis summary odds ratio must exceed two.”)

Linda Bailey, et al., “Reference Guide on Epidemiology,” in Reference Manual on Scientific Evidence at 121, 168-69 (Federal Judical Ctr. 1^st ed. 1994) (“The threshold for concluding that an agent was more likely the cause of a disease than not is a relative risk greater than 2.0 … .  A relative risk greater than 2.0 would permit an inference that an individual plaintiff’s disease was more likely than not caused by the implicated agent.”)

Ben Armstrong & Gilles Theriault, “Compensating Lung Cancer Patients Occupationally Exposed to Coal Tar Pitch Volatiles,” 53 Occup. Envt’l Med. 160 (1996)

Philip E. Enterline, “Toxic Torts:  Are They Poisoning Scientific Literature?” 30 Am. J. Indus. Med. 121 (1996)

Joseph V. Rodricks & Susan H. Rieth, “Toxicological Risk Assessment in the Court:  Are Available Methodologies Suitable for Evaluating Toxic Tort and Product Liability Claims?,” 27 Reg. Toxicol. & Pharmacol. 21, 25-30 (1998)

Michael Green et al., “Reference Guide on Epidemiology,” in Reference Manual on Scientific Evidence 333, 381, 383 (Federal Judicial Center ed., 2d ed. 2000), available at http://www.fjc.gov ( “[E]pidemiology addresses whether an agent can cause a disease, not whether an agent did cause a specific plaintiff’s disease.  * * *  Nevertheless, the specific causation issue is a necessary legal element in a toxic substance case. The plaintiff must establish not only that the defendant’s agent is capable of causing disease but also that it did cause the plaintiff’s disease.  Thus, a number of courts have confronted the legal question of what is acceptable proof of specific causation and the role that epidemiologic evidence plays in answering that question. This question is not a question that is addressed by epidemiology. Rather, it is a legal question a number of courts have grappled with.”) (“[t]he civil burden of proof is described most often as requiring the fact finder to believe that what is sought to be proved is more likely true than not true. The relative risk from epidemiologic studies can be adapted to this 50% plus standard to yield a probability or likelihood that an agent caused an individual’s disease.”)

David W. Barnes, “Too Many Probabilities:  Statistical Evidence of Tort Causation,” 64 Law and Contemp. Problems 191, 206 (2001) (criticizing the uncritical use of a relative risk greater than two to signify the probability, but acknowledging that sometimes a credible, precise RR, greater than 1.0, will be too small to support specific causation, such as the RR of 1.24 seen in the Allison case)

Russellyn S. Carruth & Bernard D. Goldstein, “Relative Risk Greater than Two in Proof of Causation in Toxic Tort Litigation,” 41 Jurimetrics 195 (2001) (criticizing the use of a relative risk of two benchmark, but acknowledging that when a disease has multiple causes and a substantial base rate in the general population, “there is no objective means to determine if a particular person’s disease was caused by some other environmental exposure, or by a non-environmental cause.”)

Richard W. Clapp & David Ozonoff, “Environment and Health:  Vital Intersection or Contested Territory?” 36 Am. J. L. & Med. 189, 210 (2004)( incorrectly describing the meaning of a confidence interval:  “A relative risk of 1.8, with confidence interval of 1.3 to 2.9 could very likely represent a true relative risk greater than 2.0, and as high as 2.9 in 95 out of 100 repeated trials.”)

Erica Beecher-Monas, Evaluating Scientific Evidence 58, 67 (N.Y. 2007)(“No matter how persuasive epidemiological or toxicological studies may be, they could not show individual causation, although they might enable a (probabilistic) judgment about the association of a particular chemical exposure to human disease in general.”)(“While significance testing characterizes the probability that the relative risk would be the same as found in the study as if the results were due to chance, a relative risk of 2 is the threshold for a greater than 50 percent chance that the effect was caused by the agent in question.”)(incorrectly describing significance probability as a point probability as opposed to tail probabilities)

Andrew W. Jurs, “Daubert, Probabilities and Possibilities and the Ohio Solution:  A Sensible Approach to Relevance Under Rule 702 in Civil and Criminal Applications,” 41 Akron L. Rev. 609, 637 (2008)(acknowledging that relative risks less than 2.0 invite jury speculation about individual, specific causation)

The relative risk argument is simple.  A relative risk of 1.0 means that the rate of disease incidence or mortality is the same among the exposed and control populations.  A relative risk of 2.0 means that the incidence rate in the exposed population is twice that in the controls.  The existence of an observed rate among the non-exposed controls suggests that we are dealing with a disease of “ordinary life,” for which there is an expected rate of occurrence.  Most chronic diseases, such as cancer, autoimmune disease, cardiovascular diseases, fall into this category of diseases of ordinary life.

If a study of a disease that is prevalent in the general population, say colon cancer, is conducted in an exposed cohort of workers, say asbestos insulators, and the study finds a relative risk of 1.5, we would have to take several steps to assess the finding’s relevance in litigation.  First, this positive association would have to be evaluated for causality.  Bias and confounding would have to be ruled out as explaining the apparent increase in risk.  Furthermore, the association would have to be evaluated for various indicia of causality, such as consistency with other studies, dose-response relationship between exposure and outcome, biological plausibility and coherence, and support from experimental studies.  In the case of asbestos and colon cancer, the causal hypothesis has repeated failed to be supported by such evaluations, but even if we were to assume general causation, arguendo, we would be left without a way to infer causation in a given case.  If plaintiff supported his case with evidence or a relative risk of 1.5, we would have 50% more observed cases than expected.  So if the observed population was expected to experience 100 colon cancer cases over the observation period, a relative risk of 1.5 means that 150 such cases were observed, or 100 expected cases and 50 putative excess cases.  Alas, there is no principled way to tell an excess case from an expected case, and the odds favor the defense two to one that any given case arose from the expected population as opposed to the excess group.  As a probability, the probability that plaintiff’s case arose from the excess portion is 33%, well below what is needed to support a sustainable claim.  Again, this assumes many facts in plaintiff’s favor, such as a perfect epidemiologic study, without bias or confounding, and with consistency among the findings of similar studies.  (None of these assumptions is even close to satisfied for asbestos and colon cancer.)

In the Agent Orange litigation, Judge Weinstein implicitly recognized the problem that very large relative risks suggested that an individual case was likely to have been related to its antecedent risks.  Small relative risks suggested that any inference of specific causation from the antecedent risk was largely speculative, in the absence of some reliable marker of exposure-related causation. See In re Agent Orange Product Liab. Litig., 597 F. Supp. 740, 785, 817 (E.D.N.Y. 1984)(plaintiffs must prove at least a two-fold increase in rate of disease allegedly caused by the exposure), aff’d, 818 F.2d 145, 150-51 (2d Cir. 1987)(approving district court’s analysis), cert. denied sub nom. Pinkney v. Dow Chemical Co., 484 U.S. 1004  (1988); see also In re “Agent Orange” Prod. Liab. Litig., 611 F. Supp. 1223, 1240, 1262 (E.D.N.Y. 1985)(excluding plaintiffs’ expert witnesses), aff’d, 818 F.2d 187 (2d Cir. 1987), cert. denied, 487 U.S. 1234 (1988). 

Ever since Judge Weinstein embraced the relative risk of two, as an important benchmark to be exceeded if plaintiffs hoped to show specific causation, scientists who practice medicine for the redistribution of wealth have attacked the concept.  The challengers have urged that small relative risks, including relative risks of two or less, could suffice to support causal attribution in a given case, especially in the presence of relevant clinical findings.  The challengers, however been vague and evasive when it comes to identifying what are the relevant clinical findings and how they operate to show that the risk has actually operated to become part of the causal pathway that has led to the individual’s injury or disease.

Among the most vociferous of the challengers has been Professor Sander Greenland, of the University of California Los Angeles School of Public Health.  Greenland has published his criticisms of the inference of a probability of individual causation from the relative risk on many occasions.  See, e.g., Sander Greenland & James Robins, “Conceptual Problems in the Definition and Interpretation of Attributable Fractions,” 128 Am. J. Epidem. 1185 (1988); James Robins & Sander Greenland, “The Probability of Causation Under a Stochastic Model for Individual Risk,” 45 Biometrics 1125 (1989); James Robins & Sander Greenland, “Estimability and Estimation of Excess and Etiologic Fractions,” 8 Statistics in Medicine 845 (1989); James Robins & Sander Greenland, “Estimability and Estimation of Expected Years of Life Lost Due to a Hazardous Exposure,” 10 Statistics in Medicine 79 (1991); Jan Beyea & Sander Greenland, “The Importance  of Specifying the Underyling Biologic Model in Estimating the Probability of Causation,” 76 Health Physics 269 (1999; Sander Greenland, “Relation of Probability of Causation to Relative Risk and Doubling Dose:  A Methodologic Error That Has Become a Social Problem,” 89 Am. J. Pub. Health 1166 (1999); Sander Greenland & James Robins, “Epidemiology, Justice, and the Probability of Causation,” 40 Jurimetrics 321 (2000).

Greenland’s criticisms turn on various assumptions such as the risk may not be evenly distributed within the sampled population, or the causal mechanism may accelerate onset of disease in such a way as to leave the relative risk unchanged in the study under consideration.  Greenland is correct that it is important to have a clear causal model in mind when evaluating the possibility of causal attributions in the light of population studies and their measures of relative risk.  He is also correct that his clever assumptions, if true, could affect the reasonableness of claiming that a relative risk of two or less supports the defense position in many toxic tort cases.  Unfortunately, Greenland’s clever assumptions and his arguments prove too much, because in many, if not most, cases the causal model is not defined.  There is often no evidence to support the plaintiffs’ claims of acceleration, or of sequestration of risk within the sampled population, and certainly no basis for claiming that the plaintiff belongs to a subset of “vulnerable” exposed persons with a higher than average risk that is reflected in the study relative risk.  Without evidence to support Greenland’s various assumptions, even higher relative risks than 2.0, say risks in the range of 2.0 to 20.0, would be unhelpful to support a plaintiffs’ case.  We would be thrown back to the early case law that held that risk can never support individual attributions, and Judge Weinstein’s rather pragmatic pronouncement in Agent Orange would be thrown aside, to the benefit of defendants in toxic tort cases. 

Last year, the Vermont Supreme Court reaffirmed the continuing vitality of the relative risk argument, on the original pragmatic justification offered by Judge Weinstein in the Agent Orange cases.  George v. Vermont League of Cities and Towns, 2010 Vt. 1, 993 A.2d 367 (Vt. 2010).  Indeed, George may well have been one of the best, and the least unheralded, decisions of 2010.

Mr. George had been a fireman before he died of non-Hodgkin’s lymphoma (NHL).  In administrative workman’s compensation proceedings, the Commissioner ruled that widow failed to show a causal connection between firefighting and NHL, although there was an “association.” His widow appealed the denial of benefits.  On de novo review, the trial court excluded plaintiffs’ expert witnesses on Rule 702 grounds.  (Vermont law follows federal law on requiring relevance and reliability of expert witnesses’ opinions.) The case ended up before the Vermont Supreme Court, which had to review the trial court’s handling of the Rule 702 issues.

Several issues were at play.  The plaintiff had presented multiple expert witnesses, Drs. Tee Guidotti and James Lockey, who had presented general and/or specific causation opinions on firefighting and NHL.  These witnesses relied upon epidemiologic studies, some of which had been incorporated into a meta-analysis, and a so-called “weight of the evidence” methodology.

The Vermont Supreme Court recognized the limits of using epidemiology to resolve the specific causation question in George. The Court found the Texas Supreme Court’s treatment of this issue to be persuasive: 

“epidemiological studies can assist in demonstrating a general association between a substance and a disease or condition, but they cannot prove that a substance actually caused a disease or condition in a particular individual.”

Id. at 374 (relying upon and quoting from Merrell Dow Pharms., Inc. v. Havner, 953 S.W.2d 706, 715 (Tex.1997)).

The Court also quoted from, and relied upon, the pronouncement of the Federal Judicial Center’s Reference Manual, which explains that ‘‘epidemiology is concerned with the incidence of disease in populations and does not address the question of the cause of an individual’s disease.  This question, sometimes referred to as specific causation, is beyond the domain of the science of epidemiology.’’ Id. at 375 (quoting from M. Green et al., “Reference Guide on Epidemiology,” in Reference Manual on Scientific Evidence 333, 381 (2d ed. 2000); footnote omitted in court’s quotation of this source).

Faced with the academic and judicial criticisms of using the relative risk (which is sometimes referred to as “effect size”), the Court recognized the pragmatic compromise between science and the needs of the legal system, embraced by using the relative risk as a benchmark showing for plaintiffs to make in toxic tort litigation:

“The trial court here adopted a relative risk factor of 2.0 as a benchmark, finding that it easily tied into Vermont’s ‘more likely than not’ civil standard and that such a benchmark was helpful in this case because the eight epidemiological studies relied upon by claimant’s experts reflected widely varying degrees of relative risk.”

 Id. at 375.

“Given claimant’s burden of proof, however, and the inherent limitations of epidemiological data in addressing specific causation, the trial court reasonably found the 2.0 standard to be a helpful benchmark in evaluating the epidemiological evidence underlying Dr. Guidotti’s opinion.”

Id. at 377.

“Mindful of this balance, we conclude that the trial court did not abuse its discretion in considering a relative risk greater than 2.0 as a reasonable and helpful benchmark under the circumstances presented here.”

 Id. at 378.

 The Vermont Supreme Court was also clearly worried about how and why plaintiff’s expert witnesses selected some studies to include in their “weight of evidence” methodology.  Without an adequate explanation of selection and weighting criteria, the choices seemed like arbitrary “cherry picking.”  Id. at 389. This worry is amply justified.  Weight of the evidence methodology is notoriously vague and indeterminate; unless the criteria for weighting are pre-specified and rigorously followed, claims based upon this methodology may be little more than subjective preferences. See, e.g., Douglas L.Weed, “Weight of Evidence: A Review of Concept and Methods,” 25 Risk Analysis 1545 (2005). 

In part, plaintiff’s expert witnesses also relied upon a meta-analysis of observational studies that looked at NHL risk among firefighters.  The Court was concerned about the plaintiffs’ expert witnesses’ failure to explain selection and weighting of studies in the meta-analysis methodology.  This criticism may well be simply plaintiff’s witnesses’ failure to explain the methodology of a published study, which in turn may have properly used an acceptable methodology to provide a summary estimate of risk of NHL among firefighters.  The meta-analysis in question, however, appears to have found a summary risk estimate of 1.51, with a 95% confidence interval, 1.31-1.73.  G.K. LeMasters, et al., “Cancer risk among firefighters: a review and meta-analysis of 32 studies,” 48 J. Occup. Envt’l Med. 1189 (2006).  The plaintiff’s expert witnesses were thus relying upon a study that quantifying the increased risk at 51%, with an upper bound from sampling variability, at 73%.  To the extent that the plaintiff had succeeded in providing reliable evidence of increased risk, she had also succeeded in showing that a doubling, or more, of the risk for NHL was statistically unlikely.  This is hardly a propitious way to win a lawsuit.

Evidence of risk is not evidence of causation.  It never has been; it never will be. Risk and causation are distinct concepts.  Processes, events, or exposures may be risks; that is, they may be capable of causing an outcome of interest.  Risk, however, is an ex ante concept.  We can speak of a risk only before the outcome of interest has occurred.  After its occurrence, we are interested in what caused the outcome.

Before the tremendous development of epidemiology in the decades after World War II, most negligence and products liability cases involved mechanistic conceptions of causation.  Juries and courts considered claims of causation that conceptually were framed in the manner of billiard balls hitting one another until the final, billiard-of-ball of interest, went into the pocket.  Litigants and courts did not need to consider statistical evidence when considering whether a saw dismembered a plaintiff, or even whether chronic asbestos exposure caused inflammation and scarring in the lungs of workers.  In some instances, judicial efforts to cast causation as a mechanistic process smack of quackery.  Claims that blunt trauma caused malignant tumors at the site of the trauma, within days or weeks of the impact, come to mind as an example of magical thinking that plagued courts and juries in a era that was short on scientific gatekeeping, and long on deferring to clinical judgment, empty of meaningful scientific support.  See, e.g., Baker v. DeRosa, 413 Pa. 164, 196 A.2d 387 (1964)(holding that question whether car accident caused tumor was for the jury).

The advent of epidemiologic evidence introduced an entirely different class of claims, ones that were based upon stochastic concepts of causation.  The exposure, event, or process that was a putative cause had a probabilistic element to its operation.  The putative cause exercised its contribution to the outcome through a random process, which left changed the frequency of the harmful outcome in those who encountered the exposure.  In addition, the outcome that resulted from the “putative cause” was frequently indistinguishable from those outcomes that arose spontaneously or from other causes in the environment or from normal human aging.  Discerning which risks (or “putative causes”) operated in a given case of chronic human disease (such cancer, cardiovascular disease, autoimmune disease) became a key issue for courts and litigants’ expert witnesses.  The black box of epidemiology, however, sheds little or no light on the issue, and no other light source was available.

Today, expert witnesses, typically for plaintiffs, equate risk with causation.  Because risk is an ex ante concept, the inference from risk to causation is problematic.  In rare instances, the risk is absolute under the circumstances of the plaintiff’s manifestation, such that the outcome can be tied to the exposure that created the risk.  In most cases, however, there will have been other competing risks, which alone could have operated to produce the outcome of which the plaintiff complains.  In toxic tort litigation, we frequently see a multiplicity of pre-existing risks for a chronic disease that is prevalent in the entire population.  When claimants attempt to show causation for such outcomes by epidemiologic evidence, the inference of causation from a particular prior risk is typically little more than a guess.

One well-known epidemiologist explained the limits of inferences with respect to stochastic causation:

“An elementary but essential principal that epidemiologists must keep in mind is that a person may be exposed to an agent and then develop disease without there being any causal connection between exposure and disease.”   ****

“In a courtroom, experts are asked to opine whether the disease of a given patient has been caused by a specific exposure.  This approach of assigning causation in a single person is radically differentfrom the epidemiologic approach, which does not attempt to attribute causation in any individual instance.  Rather, the epidemiologic approach is to evaluate the proposition that the exposure is a cause of the disease in a theoretical sense, rather than in a specific person.”

Kenneth Rothman, Epidemiology: An Introduction 44 (Oxford 2002)(emphasis added). 

Another epidemiologist, who wrote the chapter in the Federal Judicial Center’s Reference Manual on Scientific Evidence, on epidemiology, put the matter thus:

“Epidemiology answers questions about groups, whereas the court often requires information about individuals.”

Leon Gordis, Epidemiology 3d ed. (Philadelphia 2004)(emphasis in original).  Accord G. Friedman, Primer of Epidemiology 2 (2d ed. 1980 (epidemiologic studies address causes of disease in populations, not causation in individuals); Sander Greenland, “Relation of the Probability of Causation to Relative Risk and Doubling Dose:  A Methodologic Error that Has Become a Social Problem,” 89 Am. J. Pub. Health1166, 1168 (1999)(“[a]ll epidemiologic measures (such as rate ratios and rate fractions) reflect only the net impact of exposure on a population”); Joseph V. Rodricks & Susan H. Rieth, “Toxicological Risk Assessment in the Courtroom:  Are Available Methodologies Suitable for Evaluating Toxic Tort and Product Liability Claims?” 27 Regulatory Toxicol. & Pharmacol. 21, 24-25 (1998)(noting that a population risk applies to individuals only if all persons within the population are the same with respect to the influence of the risk on outcome).

These cautionary notes are important reminders of the limits of epidemiologic method.  What these authors miss is that there may be no other principled way to connect one pre-existing risk, among several, to an outcome that is claimed to be tortious.  As the young, laconic Wittgenstein wrote: 

“Wovon man nicht sprechen kann, darüber muß man schweigen.” 

L. Wittgenstein, Tractatus Logico-Philosophicus, Proposition 7 (1921)(translated by Ogden as “Whereof one cannot speak, thereof one must be silent”).  Unfortunately, expert witnesses in legal proceedings sometimes do not feel the normative force of Wittgenstein’s Proposition 7, and they speak without restraint.  As a contemporary philosopher explained in a more accessible idiom,

“Bullshit is unavoidable whenever circumstances require someone to talk without knowing what he is talking about.  Thus the production of bullshit is stimulated whenever a person’s obligations or opportunities to speak about some topic exceed his knowledge of the facts that are relevant to that topic.”

Harry Frankfurt, On Bullshit 63 (Princeton University Press 2005).

In writing previously about the Avandia MDL Court’s handling of the defendants’ Daubert motion, I noted the trial court’s erroneous interpretation of statistical evidence.  See “Learning to Embrace Flawed Evidence – The Avandia MDL’s Daubert Opinion” (Jan. 10, 2011).  In fact, the Avandia court badly misinterpreted the meaning of a p-value, a basic concept in statistics:

“The DREAM and ADOPT studies were designed to study the impact of Avandia on prediabetics and newly diagnosed diabetics. Even in these relatively low-risk groups, there was a trend towards an adverse outcome for Avandia users (e.g., in DREAM, the p-value was .08, which means that there is a 92% likelihood that the difference between the two groups was not the result of mere chance).”

In re Avandia Marketing, Sales Practices and Product Liability Litigation, 2011 WL 13576, *12 (E.D. Pa. 2011) (internal citation omitted).  The Avandia MDL court was not, however, the first to commit this howler.  Professor David Kaye collected examples of statistical blunders from published cases in a 1986 law review, and again in his chapter on statistical evidence in the Federal Judicial Center’s Reference Manual on Scientific Evidence created a list of erroneous interpretations:

United States v. Georgia Power Co., 474 F.2d. 906, 915 (5^th Cir. 1973)

National Lime Ass’n v. EPA, 627 F.2d 416, 453 (D.C. Cir. 1980)

Rivera v. City of Wichita Falls, 665 F.2d 531, 545 n.22 (5th Cir. 1982) (“A variation of two standard deviations would indicate that the probability of the observed outcome occurring purely by chance would be approximately five out of 100; that is, it could be said with a 95% certainty that the outcome was not merely a fluke.”);

Vuyanich v. Republic Nat’l Bank, 505 F. Supp. 224, 272 (N.D. Tex. 1980) (“[I]f a 5% level of significance is used, a sufficiently large t-statistic for the coefficient indicates that the chances are less than one in 20 that the true coefficient is actually zero.”), vacated, 723 F.2d 1195 (5th Cir. 1984)

Craik v. Minnesota State Univ. Bd., 731 F.2d 465, 476n.13 (8^th Cir. 1984)(“[a] finding that a disparity is statistically significant at the 0.095 or 0.01 level means that there is a 5 per cent. Or 1 per cent. Probability, respectively, that the disparity is due to chance.”  See also id. at 510 (Swygert, J., dissenting)(stating that coefficients were statistically significant at 1% level, allowing him to say that “we can be 99% confident that each was different from zero.”)

Sheehan v. Daily Racing Form, Inc., 104 F.3d 940, 941 (7th Cir. 1997) (“An affidavit by a statistician . . . states that the probability that the retentions . . . are uncorrelated with age is less than 5 percent.”)

Waisome v. Port Authority, 948 F.2d 1370, 1376 (2d Cir. 1991) (“Social scientists consider a finding of two standard deviations significant, meaning there is about one chance in 20 that the explanation for a deviation could be random . . . .”)

David H. Kaye & David A. Freedman, “Reference Guide on Statistics,” in Reference Manual on Scientific Evidence 83, 122-24 (2^nd ed. 2000); David H. Kaye, “Is Proof of Statistical Significance Relevant?” 61 Wash. L. Rev. 1333, 1347 (1986)(pointing out that before 1970, there were virtually no references to “statistical significance” or p-values in reported state or federal cases. 

Notwithstanding the educational efforts of the Federal Judicial Center, the innumeracy continues, and with the ascent of the MDL model for addressing mass torts, many recent howlers have come from trial judges given responsibility for overseeing the pretrial coordination of thousands of lawsuits.  In addition to the Avandia MDL Court, here are some other recent erroneous statements that can be added to Professor Kaye’s lists: 

“Scientific convention defines statistical significance as “P ≤ .05,” i.e., no more than one chance in twenty of a finding a false association due to sampling error.  Plaintiffs, however, need only prove that causation is more-probable-than-not.”

In re Ephedra Prods. Liab. Litig., 393 F.Supp.2d 181, 193 (S.D.N.Y. 2005)(confusing the standard for Type I statistical error with the burden of proof).

“More-probable-than-not might be likened to P < .5, so that preponderance of the evidence is nearly ten times less significant (whatever that might mean) than the scientific standard.”

Id. at 193 n.9 (same). 

In the Phenylpropanolamine litigation, the error was even more clearly stated, for both p-values and confidence intervals:

“P-values measure the probability that the reported association was due to chance… .”

“… while confidence intervals indicate the range of values within which the true odds ratio is likely to fall.”

In re Phenylpropanolamine Products Liab. Litig., 289 F. 2d 1230, 1236n.1 (2003)

These misstatements raise important questions about judicial competency for gatekeeping, the selection, education, and training of judges, the assignment of MDL cases to individual trial judges, and the aggregation of Rule 702 motions to a trial judge for a single, one-time decision that will control hundreds if not thousands of cases.

Recently, a student published a bold note that argued for the dismantling of judicial gatekeeping.  Note, “Admitting Doubt: A New Standards for Scientific Evidence,” 123 Harvard Law Review 2021 (2010).  With all the naiveté of someone who has never tried a jury trial, the student argued that juries are at least as good, if not better, at handling technical questions.  The empirical evidence for such a suggestion is slim, and ignores the geographic variability in jury pools.  The above instances of erroneous statistical interpretations might seem to support the student’s note, but the argument would miss two important points: 

• these errors are put on display for all to see, and for commentators to note and correct, whereas jury decisions obscure their mistakes; and
• judges can be singled out for their technical competencies, and given appropriate assignments (which hardly ever happens at present), and judges can be required to partake in professional continuing legal education, which might well include training in technical areas to improve their decision making.

The Federal Judicial Center, and its state court counterparts, have work to do.  Lawyers also have an obligation to help courts get difficult, technical issue right.  Finally, courts, lawyers, and commentators need to rethink how the so-called Daubert process works, and does not work, especially in the high-stakes arena of multi-district litigation.

The so-called Daubert process, by which each side in a lawsuit may challenge and seek preclusion of the other side’s expert witnesses, arose in the setting of common-law judges making rulings in individual cases.  Indeed, the Daubert case itself, although one of many cases involving claims of birth defects allegedly caused by Bendectin, was an individual case. 

In the silicone gel breast implant (SGBI) litigation, the process evolved over time, with decisions from different judges, each of whom saw the evidence differently.  The different judges brought different insights and aptitudes to bear on the evidence, and the expert witnesses themselves may have varied in their approaches and reliance upon different studies.  This incrementalist approach, in the context of the SBGI litigation, worked to the benefit of the defendants, in part because their counsel learned about the fraudulent evidence underlying certain studies, and about serious lapses in the standard of research care on the part of some investigators whose studies were prominently relied upon by plaintiffs’ counsel.  In the case of one dubious study, one of its authors, Marc Lappe, a prominent expert witness for plaintiffs, withdrew his support from the conclusions advanced in the study.

Early decisions in the SGBI cases (shortly after the Supreme Court’s decision in Daubert, in 1993) denied the defendants’ applications to preclude plaintiffs’ expert witnesses’ opinion testimony.  Later decisions converged upon the unavoidable truth that the case for SGBIs causing atypical or typical connective tissue diseases was a house of cards, built mostly with jokers.  If the Daubert process had been censored after the first hearing, the result would have been to deem all the breast implant cases trial and jury worthy, to the detriment of the judicial process, to the public’s interest in knowing the truth about silicone biomaterials, to the defendants’ reputational and financial interests, and to the interests of the claimants who had been manipulated by their counsel and support group leaders.

The evolutionary approach taken in the SGBI litigation was indirectly supported by the late Judge Sam Pointer, who presided over the SGBI federal multi-district litigation (MDL).  Judge Pointer strongly believed that the decision to exclude expert testimony belonged to individual trial judges, who received cases on remand from the MDL 926, when the cases were ready for trial.  Judge Pointer ruled on expert witness challenges in cases set for trial before him, but he was not terribly enthusiastic about the Daubert process, and denied most of the motions in a fairly perfunctory fashion.  Because of this procedural approach, Judge Pointer’s laissez-faire attitude towards expert witness testimony did not interfere with the evolutionary process that allowed other courts to see through the dense fog in the plaintiffs’ case.

Since MDL 926, the MDL process has absorbed the ritual of each side’s challenging the other’s expert witnesses, and MDL judges view their role as including the hearing and deciding all pre-trial Daubert challenges.  It has been over 17 years since the Supreme Court decided Daubert, and in that time, the MDL model, both state and federal, has become dominant.  As a result, the Daubert process has often been truncated and abridged to a single motion, decided at one time, by one judge.  The results of this abridgement have not always been happy for ensuring reliable and accurate gatekeeping. 

The MDL process appears to have broken the promise of Rule 702 in many cases.  By putting the first and only Rule 702 gatekeeping decision in the hands of a single judge, charged with making pre-trial rulings in the entire MDL, the MDL process has sapped the gatekeeping process of its dynamic, evolutionary character.  No longer can litigants and judges learn from previous efforts, as well as from commentary by scientists and legal scholars on the prior outcomes.  For judges who lack scientific and analytical acumen, this isolation from the scientific community works to the detriment of the entire process.

To be sure, the MDL process for deciding Rule 702 is efficient.  In many cases, expensive motions, briefings, and hearings are reduced to one event.  The incorporation of expert challenges into an MDL may improve fairness in some instances by allowing well-qualified plaintiffs’ counsel to wrest control of the process from unprepared plaintiffs’ counsel who are determined to control their individual cases.  Defendants may embrace the MDL process because it permits a single, unified document production and discovery schedule of corporate executives.  Perhaps defendants see the gains from MDL process as sufficiently important to forgo the benefit of a fuller opportunity to litigate the expert witness issues.  Whatever can be said in favor of using the MDL forum to resolve expert witness challenges, it is clear that MDL procedures limit the parties’ ability to refine their challenges over time, and to incorporate new evidence and discovery gained after the first challenges are resolved.  In the SGBI litigation, for instance, the defendants learned of significant scientific malfeasance and misfeasance that undermined key studies relied upon by plaintiffs, including some studies done by apparently neutral, well-credential scientists.  The omnibus MDL Daubert motion prevents either side, or the judiciary, from learning from the first and only motion.

Another example of an evidentiary display that has changed over time comes from the asbestos litigation, where plaintiffs continue to claim that asbestos causes gastrointestinal cancer.  The first such cases were pressed by plaintiffs in the early 1980s, with the support of Dr Selikoff and his cadre of testifying physicians and scientists.  A few years ago, however, the Institutes of Medicine convened a committee to review non-pulmonary cancers and asbestos, and concluded that the studies, now accumulated over 35 years since Dr Selikoff’s ipse dixit, do not support a conclusion that asbestos causes colorectal cancer.  Institute of Medicine of the National Academies, Asbestos: Selected Health Effects (2006).

Unfortunately, many trial judges view the admissibility and sufficiency of causation opinions on asbestos and colorectal cancer as “grandfathered” by virtue of the way business has been conducted in trial courts for over three decades.  Still, defendants have gained the opportunity to invoke an important systematic review, which shows that the available evidence does not reliably support the conclusion urged by plaintiffs’ expert witnesses. 

The current approach of using the MDL as the vehicle for resolving expert witness challenges raises serious questions about how MDLs are assigned to judges, and whether those judges have the analytical or quantitative skills to resolve Daubert challenges.  Assigning an MDL to a judge, who will have to rule on the admissibility of expert witness opinion testimony she or he does not understand, does not inspire confidence in the judicial process.  At least in the ad hoc approach employed in the SGBI, the parties could size up their trial judge, and decide that they would forgo their expert challenges based upon their assessment.  Furthermore, an anomalous outcome could be corrected over a series of decisions.  The MDL process, on the other hand, frequently places the Rule 702 decision in the discretion of a single judge.  The selection criteria for that sole decision maker becomes critical.  As equity in days of old varied with the size of the Chancellor’s foot, today’s scientific equity under Rule 702 may vary with accuracy of the trial judge’s slide rule.

For GSK, the other shoe dropped in the Avandia multi-district litigation, on January 13, 2011, when the presiding judge denied the defense challenge to plaintiff’s expert witness specific causation opinions, in the first case set for trial.  Burford v. GlaxoSmithKline, PLC, 2011 WL 135017 (E.D.Pa. 2011). 

In the MDL court’s opinion on general causation, In re Avandia Marketing, Sales Practices and Product Liability Litigation, 2011 WL 13576 (E.D. Pa. 2011), Judge Rufe determined that she was bound to apply a “Third Circuit” approach to expert witness gatekeeping, which focused on the challenged expert witnesses’ methodology, not their conclusions.  In Burford, Judge Rufe, citing two Third Circuit cases were decided after Daubert, but before Joiner, repeats this basic mistake.  Burford, 2011 WL 135017, *2.  Remarkably, the court’s opinion in Burford recites the current version of Federal Rule of Evidence 702, which states that the court must analyze expert witnesses’ conclusions for being based upon “sufficient facts or data,” as well as for being “the product of reliable principle and methods.” The statute mandates consideration of the reliability and validity of the witness’s conclusions, if those conclusion are in his testimony.  This Rule, enacted by Congress in 2000, is a statute, and thus supersedes prior case law, although the Advisory Notes explain that the language of the rule draws heavily from the United States Supreme Court’s decisions in Daubert, Joiner, and Kumho Tire. The Avandia MDL court ignored both the post-Daubert decisions of the Supreme Court, as well as the controlling language of the statute, in gatekeeping opinions on general and specific causation.

Two expert witnesses on specific causation were the subject of GSK’s challenge in Burford:  Dr. Nicholas DePace and Dr. Judy Melinek.  The court readily dispatches Dr. Melinek, who opines that Mr. Burford’s fatal cardiac event, which she characterizes as a heart attack, was caused by Avandia because Avandia causes heart attacks.  The court correctly noted that this inference was improper because risk does not equal causation in a specific case.

As one well-known epidemiologist has put it:

“An elementary but essential principal that epidemiologists must keep in mind is that a person may be exposed to an agent and then develop disease without there being any causal connection between exposure and disease.”

* * *

“In a courtroom, experts are asked to opine whether the disease of a given patient has been caused by a specific exposure.  This approach of assigning causation in a single person is radically different from the epidemiologic approach, which does not attempt to attribute causation in any individual instance.  Rather, the epidemiologic approach is to evaluate the proposition that the exposure is a cause of the disease in a theoretical sense, rather than in a specific person.”

Kenneth Rothman, Epidemiology: An Introduction 44 (Oxford 2002)(emphasis added).

In addressing the admissibility of Dr. DePace’s expert opinion, however, the MDL Court is led astray by Dr. DePace’s handwaving about having considered and “ruled out” Mr. Burford’s other risk factors. 

To be sure, Dr. DePace has some ideas about how Avandia may, plausibly, cause heart attacks.  In particular, Dr. DePace identified three plausible mechanisms, each of which would have had been accompanied by some biomarker (elevated blood lipids, elevated Lp-PLA2, or hypoglycemia).  This witness, however, could not opine that any of these mechanisms was in operation in producing Mr. Burford’s fatal cardiac event. Burford, at *3.

Undaunted, Dr. DePace opined that he had ruled out Mr. Burford’s other risk factors, but his opinion, even from Judge Rufe’s narrative is clearly hand waving and dissembling.  First, everyone, including every middle age man, has a risk of heart attack or cardiac arrest, although that risk may be modified – increased or lowered – by risks or preventive factors.  Mr. Burford had severe diabetes, which in and of itself, is a risk factor, commonly recognized to equal the size of the risk from having had a previous heart attack.  So Mr. Burford was not at baseline risk; indeed, he started all his diabetes medications with the equivalent risk of someone who had had a heart attack already.

Dr. DePace apparently opined that Mr. Burford’s diabetes, his blood sugar level, was well controlled.  The court accepted this contention at face value, although the reader of the court’s opinion will know that it is rubbish.  Although the court does not recite any blood sugar levels, its narrative of facts includes the following course of medications for Mr. Burford:

• June 2004, diagnosed with type II diabetes, and treated with metformin
• April 2005, dose of metformin doubled
• August 2005, Avandia added to double dose of metformin
• December 2005, Avandia dose doubled as well
• June 2006, metformin dose doubled again
• October or November 2006, sulfonylurea added to Avandia and metformin

This narrative hardly suggests good control.  Mr. Burford was on a downward spiral of disease, which in a little over two years took him from diagnosis to three medications to try to control his diabetes. Despite adding Avandia to metformin, doubling the doses of Avandia, doubling and then quadrupling doses of metformin, Mr. Burford still required yet another, third medication, to achieve glycemic control.  Of course, an expert witness can say anything, but the federal district court is supposed to act as a gatekeeper, to protect juries and parties from their ipse dixit.  Many opinions will be difficult to evaluate, but here, Dr. DePace’s opinion about glycemic control in Mr. Burford comes with a banner headline, which shouts “bogus.”

The addition of a third medication, a sulfonylurea, known to cause hypoglycemia (dangerously low blood sugar), which in turn can cause cardiac events and myocardial infarction, is particularly troubling.  See “Sulfonylurea,” in Wikipedia January 24, 2011.  Sulfonylureas act by stimulating the pancreas to produce more insulin, and the sudden addition of this medication to an already aggressive regime of medication clearly had the ability to induce hypoglycemia in Mr. Burford.  Dr. DePace notes that there is no evidence of an hypoglycemic event, which is often true in diabetic patients who experience a sudden death, but the gatekeeping court should have noticed that Dr. DePace’s lack of evidence did not equate to evidence that the risk or actual causal role (of hypoglycemia) was lacking.  Again, the trial court appeared to be snookered by an expert witness’s hand waving.  Surely gatekeepers must be made of sterner stuff.

Perhaps the most wrongheaded is the MDL court’s handling, or its failure to handle, risk as causation, in Dr. DePace’s testimony.

In his deposition, Dr. DePace testified that a heart attack in a 49 year-old man was “very unusual.”  Such a qualitative opinion does not help the finder of fact.  A heart attack is more likely in any 49 year-old man than in any 21 year-old man, although men of both ages can and do suffer heart attacks.  Clearly, a heart attack is more likely in a 49-year old man who has had diabetes, which has required intensive medication for even a semblance of control, than in a 49 year-old man who has never had diabetes.  Dr. DePace’s opinions fail to show that Mr. Burford had no base-line risk in absence of one particular medication, or that this base-line risk was not operating to produce, sufficiently, his alleged heart attack. 

Rather than being a high-risk group with respect to his Avandia use, according to the FDA’s 2007  meta-analysis, Mr. Burford and other patients on “triple therapy” (Avandia + metformin + sulfonylurea), would have had an odds ratio of 1.1 for any myocardial ischemic event, not statistically significant, as a result of their Avandia use.  Mr. Burford’s additional use of an ACE-inhibitor, along with this three diabetic medications, would place him into yet another sub-subgroup.  Whatever modification or interaction this additional medication created in combination with Avandia, the confidence intervals, which were wide for the odds ratio of 1.1, would  become extremely wide, allowing no meaningful inference. In any event, the court in Burford does not tell us what the risk was opined to be, and whether there were good data and facts to support such an opinion.  Remarkably absent from the court’s opinion in Burford is any consideration of the actual magnitude of the claimed risk (in terms of a hazard ratio, relative risk, odds ratio, risk difference, etc.) for patients like Mr. Burford.  Further absent is any consideration of whether any study showing risk has further shown the risk to be statistically different from 1.0 (no increased risk at all). 

As Ted Frank has noted on PointofLaw Forum, the Avandia MDL raises serious questions about the allocation of technical multi-district litigation cases to judges in the federal system.  “It is hard to escape the conclusion that the MDL denied GSK intellectual due process of law” (January 21, 2011).  The Avandia experience also raises questions about the efficacy of the Federal Judicial Center’s program to train judges in the basic analytical, statistical, and scientific disciplines needed in their gatekeeping capacity. 

Although the Avandia MDL court’s assessment that Dr. DePace’s opinion was suboptimal, Burford at * 4, may translate into GSK’s ability to win before a jury, the point of Rule 702 is that a party should not have to stand trial on such shoddy evidence.