Reference Manual on Scientific Evidence on Relative Risk Greater Than Two For Specific Causation Inference

The first edition of the Reference Manual on Scientific Evidence [Manual] was published in 1994, a year after the Supreme Court delivered its opinion in Daubert. The Federal Judicial Center organized and produced the Manual, in response to the kernel panic created by the Supreme Court’s mandate that federal trial judges serve as gatekeepers of the methodological propriety of testifying expert witnesses’ opinions. Considering the intellectual vacuum the Center had to fill, and the speed with which it had to work, the first edition was a stunning accomplishment.

In litigating specific causation in so-called toxic tort cases, defense counsel quickly embraced the Manual’s apparent endorsement of the doubling-of-the-risk argument, which would require relative risks in excess of two in order to draw inferences of specific causation in a given case. See Linda A. Bailey, Leon Gordis, and Michael D. Green, “Reference Guide on Epidemiology,” in Federal Judicial Center, Reference Manual on Scientific Evidence 123, 150, 168 (Washington, DC:, 1st ed., 1994) (“The relative risk from an epidemiological study can be adapted to this 50% plus standard to yield a probability or likelihood that an agent caused an individual’s disease. The threshold for concluding that an agent was more likely than not the cause of a disease than not is a relative risk greater than 2.0.”) (internal citations omitted).

In the Second Edition of the Manual, the authorship of the epidemiology chapter shifted, and so did its treatment of doubling of the risk. By adopting a more nuanced analysis, the Second Edition deprived defense counsel of a readily citable source for the proposition that low relative risks do not support inferences of specific causation. The exact conditions for when and how the doubling argument should prevail were, however, left fuzzy and unspecified. See Michael D. Green, D. Michal Freedman , and Leon Gordis, “Reference Guide on Epidemiology,” in Federal Judicial Center, Reference Manual on Scientific Evidence 333, 348-49 (Wash., DC, 2d ed. 2000)

The latest edition of the Manual attempts to correct the failings of the Second Edition by introducing an explanation and a discussion of some of the conditions that might undermine an inference, or opposition thereto, of specific causation from magnitude of relative risk. Michael D. Green, D. Michal Freedman, and Leon Gordis, “Reference Guide on Epidemiology,” in Federal Judicial Center, Reference Manual on Scientific Evidence 549, 612 (Wash., DC 3d ed., 2011).

The authors of the Manual now acknowledge that doubling of risk inference has “a certain logic as far as it goes,” but point out that there are some “significant assumptions and important caveats that require explication.” Id.

What are the assumptions according the Manual?

First, and foremost, there must be “[a] valid study and risk estimate.” Id. (emphasis in original). The identification of this predicate assumption is, of course, correct, but the authors overlook that the assumption is often trivially satisfied by the legal context in which the doubling argument arises. For instance, in the Landrigan and Caterinichio cases, cited below, the doubling issue arose not as an admissibility question of expert witness opinion, but on motions for directed verdict. In both cases, plaintiffs’ expert witnesses committed to opinions about plaintiffs’ being at risk from asbestos exposure, based upon studies that they identified. Defense counsel in those cases did not concede the existence of risk, the size of the risk, or the validity of the study, but rather stipulated such facts solely for purposes of their motions to dismiss. In other words, even if the plaintiffs’ relied upon studies were valid and the risk estimates accurate (with relative risks of 1.5), plaintiffs could not prevail because no reasonable jury could infer that plaintiffs’ colorectal cancers were caused by their occupational asbestos exposure. The procedural context of the doubling risk thus often pretermits questions of validity, bias, and confounding.

Second, the Manual identifies that there must be “[s]imilarity among study subjects and plaintiff.” Id. at 613. Again, this assumption is often either pretermitted for purposes of lodging a dispositive motion, conceded, or included as part of the challenge to an expert witness’s opinion’s admissibility. For example, in some litigations, plaintiffs will rely upon high-dose or high-exposure studies that are not comparable to the plaintiff’s actual exposure, and the defense may have shown that the only reliable evidence is that there is a small (relative risk less than two) or no risk at all from the plaintiff’s exposure. External validity objections may well play a role in a contest under Rule 702, but the resolution of a doubling of risk issue will require an appropriate measure of risk for the plaintiff whose injury is at issue.

In the course of identifying this second assumption, the Manual now points out that the doubling argument turns on applying “an average risk for the group” to each individual in the group. Id. This point again is correct, but the Manual does not come to terms with the challenge often made to what I call the assumption of stochastic risk. The Manual authors quote a leading textbook on epidemiology:

“We cannot measure the individual risk, and assigning the average value to everyone in the category reflects nothing more than our ignorance about the determinants of lung cancer that interact with cigarette smoke. It is apparent from epidemiological data that some people can engage in chain smoking for many decades without developing lung cancer. Others are or will become primed by unknown circumstances and need only to add cigarette smoke to the nearly sufficient constellation of causes to initiate lung cancer. In our ignorance of these hidden causal components, the best we can do in assessing risk is to classify people according to measured causal risk indicators and then assign the average observed within a class to persons within the class.”

Id at n.198., quoting from Kenneth J. Rothman, Sander Greenland, and Tim L. Lash, Modern Epidemiology 9 (3d ed. 2008). Although the textbook on this point is unimpeachable, taken at face value, it would introduce an evidentiary nihilism for judicial determinations of specific causation in cases in which epidemiologic measures of risk size are the only basis for drawing probabilistic inferences of specific causation. See also Manual at 614 n. 198., citing Ofer Shpilberg, et al., The Next Stage: Molecular Epidemiology, 50 J. Clin. Epidem. 633, 637 (1997) (“A 1.5-fold relative risk may be composed of a 5-fold risk in 10% of the population, and a 1.1-fold risk in the remaining 90%, or a 2-fold risk in 25% and a 1.1-fold for 75%, or a 1.5-fold risk for the entire population.”). The assumption of stochastic risk is, as Judge Weinstein recognized in Agent Orange, often the only assumption on which plaintiffs will ever have a basis for claiming individual causation on typical datasets available to support health effects claims. Elsewhere, the authors of the Manual’s chapter suggest that statistical “frequentists” would resist the adaptation of relative risk to provide a probability of causation because for the frequentist, the individual case either is or is not caused by the exposure at issue. Manual at 611 n.188. This suggestion appears to confuse the frequentist enterprise for evaluating evidence on the basis of statistical measures of the probability of observing at least as great a departure from expected in a sample rather than attempting to affixing a probability to the population parameter. The doubling argument derives from the well-known “urn model” in probability theory, which is not really at issue in the frequentist-Bayesian wars.

Third, the Manual authors state that the doubling argument assumes the “[n]onacceleration of disease.” In some cases, this statement is correct, but there is no evidence of acceleration, and because an acceleration-of-onset theory would diminish damages, typically defendants would have the burden of going forward with identifying the acceleration phenomenon. The authors go further, however, in stating that “for most of the chronic diseases of adulthood, it is not possible for epidemiologic studies to distinguish between acceleration of disease and causation of new disease.” Manual at 614. The inability to distinguish acceleration from causation of new cases would typically redound to the disadvantage of defendants that are making the doubling argument. In other words, the defendants would, by this supposed inability, be unable to mitigate damages by showing that the alleged harm would have occurred any way, but only later in time. See Manual at 615 n. 199 (“If acceleration occurs, then the appropriate characterization of the harm for purposes of determining damages would have to be addressed. A defendant who only accelerates the occurrence of harm, say, chronic back pain, that would have occurred independently in the plaintiff at a later time is not liable for the same amount of damages as a defendant who causes a lifetime of chronic back pain.”). More important, however, the Manual appears to be wrong that epidemiologic studies cannot identify acceleration of onset of a particular disease in an epidemiologic study or clinical trial. Many modern longitudinal epidemiologic studies and clinical trials use survival analysis and time windows to identify latency or time lagged outcomes in association with identified exposures.

The fourth assumption identified in the Manual is that the exposure under study acts independently of other exposures. The authors give the time-worn example of multiplicative synergy between asbestos and smoking, what elsewhere has been referred to as “The Mt. Sinai Catechism” (June 7, 2013). The example was improvidently chosen given that the multiplicative nature was doubtful when first advanced, and now has effectively been retracted or modified by the researchers following the health outcomes of asbestos insulators in the United States. More important for our purposes here, interactions can be quantified and added to the analysis of attributable risk; interactions are not insuperable barriers to reasonable apportiontment of risk.

Fifth, the Manual identifies two additional assumptions in that (a) the exposure at issue is not responsible for another outcome that competes with morbidity or mortality, and (b) the exposure does not provide a protective “effect” in a subpopulation of those studied. Manual at 615. On the first of these assumptions, the authors suggest that this assumption is required “because in the epidemiologic studies relied on, those deaths caused by the alternative disease process will mask the true magnitude of increased incidence of the studied disease when the study subjects die before developing the disease of interest.” Id. at 615 n.202. Competing causes, however, are frequently studied and can be treated as confounders in an appropriate regression or propensity score analysis to yield a risk estimate for each individual putative effect at issue. The second of the two assumptions is a rehash of the speculative assertion that the epidemiologic study (and the population it samples) may not have a stochastic distribution of risk. Although the stochastic assumption may not be correct, it is often favorable to the party asserting the claim who otherwise would not be able to show that he was not in a sub-population of people not affected at all, or even benefitted from the exposure. Again, modern epidemiology does not stop at identifying populations at risk, but continues to refine the assessment by trying to identify subpopulations that have the risk exclusively. The existence of multi-modal distributions of risk within a population is, again, not a barrier to the doubling argument.

With sufficiently large samples, epidemiologic studies may be able to identify subgroups that have very large relative risks, even when the overall sample under study had a relative risk under two. The possibility of such subgroups, however, should not be an invitation to wholesale speculation that a given plaintiff is in a “vulnerable” subgroup without reliable, valid evidence of what the risks for the identified subgroup are. Too often, the vulnerable plaintiff or subgroup claim is merely hand waving in an evidentiary vacuum. The Manual authors seem to adopt this hand-waving attitude when they give a speculative hypothetical example:

“For example, genetics might be known to be responsible for 50% of the incidence of a disease independent of exposure to the agent. If genetics can be ruled out in an individual’s case, then a relative risk greater than 1.5 might be sufficient to support an inference that the agent was more likely than not responsible for the plaintiff’s disease.”

Manual at 615-16 (internal citations omitted). The hypothetical is unclear whether “the genetics” cases are part of the study that yielded a relative risk of 1.5, but of course if the “genetics” were uniformly distributed in the population, and also in the sample studied in the epidemiologic study, then the “genetics” would appear to drop out of playing any role in elevating risk. But as the authors pointed out in their caveats about interaction, there may well be a role of interaction between the “genetics” and the exposure in the study such that “the genetics” cases occurred earlier or did not add anything to the disease burden that would have been caused by the exposure under study that reported out a relative risk of 1.5. So bottom line, plaintiff would need a study that applied the “genetics” to the epidemiologic study to see what relative risks might be observed in people without the genes at issue.

The Third Edition of the Manual does add more nuance to the doubling of risk argument, but alas more nuance yet is needed. The chapter is an important source to include in any legal argument for or against inferences of specific causation, but it is hardly the final word.

Below, I have updated a reference list of cases that reference the doubling argument.


Radiation

Johnston v. United States, 597 F. Supp. 374, 412, 425-26 (D. Kan. 1984) (rejecting even a relative risk of greater than two as supporting an inference of specific causation)

Allen v. United States, 588 F. Supp. 247, 418 (1984) (rejecting mechanical application of doubling of risk), rev’d on other grounds, 816 F.2d 1417 (10th Cir. 1987), cert. denied, 484 U.S. 1004 (1988)

In re TMI Litig., 927 F. Supp. 834, 845, 864–66 (M.D. Pa. 1996), aff’d, 89 F.3d 1106 (3d Cir. 1996), aff’d in part, rev’d in part, 193 F.3d 613 (3d Cir. 1999) (rejecting “doubling dose” trial court’s analysis), modified 199 F.3d 158 (3d Cir. 2000) (stating that a dose below ten rems is insufficient to infer more likely than not the existence of a causal link)

In re Hanford Nuclear Reservation Litig., 1998 WL 775340, at *8 (E.D. Wash. Aug. 21, 1998) (“‘[d]oubling of the risk’ is the legal standard for evaluating the sufficiency of the plaintiffs’ evidence and for determining which claims should be heard by the jury,” citing Daubert II), rev’d, 292 F.3d 1124, 1136-37 (9th Cir. 2002) (general causation)

In re Berg Litig., 293 F.3d 1127 (9th Cir. 2002) (companion case to In re Hanford)

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)

Cook v. Rockwell Internat’l Corp., 580 F. Supp. 2d 1071, 1083n.8, 1084, 1088-89 (D. Colo. 2006) (citing Daubert II and “concerns” by Sander Greenland and David Egilman, plaintiffs’ expert witnesses in other cases), rev’d and remanded on other grounds, 618 F.3d 1127 (10th Cir. 2010), cert. denied, ___ U.S. ___ (May 24, 2012)

Cotroneo v. Shaw Envt’l & Infrastructure, Inc., No. H-05- 1250, 2007 WL 3145791, at *3 (S.D. Tex. Oct. 25, 2007) (citing Havner, 953 S.W.2d at 717) (radioactive material)


Swine Flu- GBS Cases

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.”)

Robinson v. United States, 533 F. Supp. 320, 325-28 (E.D. Mich. 1982) (finding for the government and against claimant who developed acute signs and symptoms of GBS 17 weeks after innoculation, in part because of relative and attributable risks)

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) (incorrectly suggesting that relative risk of two means that there was a 50% chance the disease was caused by “chance alone”), aff’d in relevant part, 830 F.2d 831 (8th Cir. 1987)


IUD Cases – Pelvic Inflammatory Disease

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 (4th Cir. 1987) (per curiam)


Bendectin cases

Lynch v. Merrill-National Laboratories, 646 F.Supp. 856 (D. Mass. 1986)(granting summary judgment), aff’d, 830 F.2d 1190, 1197 (1st 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, 958-59 (3d Cir. 1990) (commenting that ‘‘[i]f New Jersey law requires the DeLucas to show that it is more likely than not that Bendectin caused Amy DeLuca’s birth defects, and they are forced to rely solely on Dr. Done’s epidemiological analysis in order to avoid summary judgment, the relative risk of limb reduction defects arising from the epidemiological data Done relies upon will, at a minimum, have to exceed ‘2’’’)

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; testimony that the drug “increased somewhat the likelihood of birth defects” is insufficient) (“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) (noting testimony by Dr. Michael Bracken, that had Bendectin doubled risk of birth defects, overall rate of that birth defect should have fallen 23% after manufacturer withdrew drug from market, when in fact the rate remained relatively steady)

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)


Silicone Cases

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, correctly but irrelevantly, 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)

Minnesota Mining and Manufacturing v. Atterbury, 978 S.W.2d 183, 198 (Tex.App. – Texarkana 1998) (noting that Havner declined to set strict criteria and 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”)

Allison v. McGhan Med. Corp., 184 F.3d 1300, 1315n.16, 1316 (11th 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) (“The relative risk is obtained by dividing the proportion of individuals in the exposed group who contract the disease by the proportion of individuals who contract the disease in the non-exposed group.”) (noting that relative risk must be more than doubled at a minimum to permit an inference that the risk was operating in plaintiff’s case)

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”)


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)

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

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)

In re Fibreboard Corp.,893 F.2d 706, 712 (5th Cir.1990) (“It is evident that these statistical estimates deal only with general causation, for population-based probability estimates do not speak to a probability of causation in any one case; the estimate of relative risk is a property of the studied population, not of an individual’s case.” (internal quotation omitted) (emphasis in original))

Grassis v. Johns-Manville Corp., 248 N.J. Super. 446, 455-56, 591 A.2d 671, 676 (App. Div. 1991) (rejecting doubling of risk threshold in asbestos gastrointestinal cancer claim)

Landrigan v. Celotex Corp., 127 N.J. 404, 419, 605 A.2d 1079 (1992) (reversing judgment entered on directed verdict for defendant on specific causation of claim that asbestos caused decedent’s colon cancer)

Caterinicchio v. Pittsburgh Corning Corp., 127 N.J. 428, 605 A.2d 1092 (1992) (reversing judgment entered on directed verdict for defendant on specific causation of claim that asbestos caused plaintiff’s colon cancer)

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, 97 (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 1124, 1134 (2d Cir. 1995) (stating a preference for the district court’s instructing the jury on the science and then letting the jury weigh the studies)

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

Jones v. Owens-Corning Fiberglas Corp., 288 N.J. Super. 258, 266, 672 A.2d 230, 235 (App. Div. 1996) (rejecting doubling of risk threshold in asbestos gastrointestinal cancer claim)

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)

Kwasnik v. A.C. & S., Inc. (El Paso Cty., Tex. 2002)

Sienkiewicz v. Greif (U.K.) Ltd., [2009] EWCA (Civ) 1159, at ¶23 (Lady Justice Smith) (“In my view, it must now be taken that, saving the expression of a different view by the Supreme Court, in a case of multiple potential causes, a claimant can demonstrate causation in a case by showing that the tortious exposure has at least doubled the risk arising from the non-tortious cause or causes.”)

Sienkiewicz v. Greif  Ltd., [2011] UKSC 10.

“Where there are competing alternative, rather than cumulative, potential causes of a disease or injury, such as in Hotson, I can see no reason in principle why epidemiological reason should not be used to show that one of the causes was more than twice as likely as all the others put together to have caused the disease or injury.” (Lord Philips, at ¶ 93)

(arguing that statistical evidence should be considered without clearly identifying the nature and extent of its role) (Baroness Hale, ¶ 172-73)

(insisting upon difference between fact and probability of causation, with statistical evidence not probative of the former) (Lord Roger, at ¶143-59)

(“the law is concerned with the rights and wrongs of an individual situation, and should not treat people and even companies as statistics,” although epidemiologic evidence can appropriately be used he identified “in conjunction with specific evidence”) (Lord Mance, at ¶205)

(concluding that epidemiologic evidence can establish the probability, but not the fact of causation, and vaguely suggesting that whether epidemiologic evidence should be allowed was a matter of policy) (Lord Dyson, ¶218-19)

Dixon v. Ford Motor Co., 47 A. 3d 1038, 1046-47 & n.11 (Md. Ct. Special Appeals 2012)(“we can explicitly derive the probability of causation from the statistical measure known as ‘relative risk’, as did the U.S. Court of Appeals for the Third Circuit in DeLuca v. Merrell Dow Pharmaceuticals, Inc., 911 F.2d 941, 958 (3d Cir.1990), in a holding later adopted by several courts. For reasons we need not explore in detail, it is not prudent to set a singular minimum ‘relative risk’value as a legal standard. But even if there were some legal threshold, Dr. Welch provided no information that could help the finder of fact to decide whether the elevated risk in this case was ‘substantial’.”)(internal citations omitted), rev’d, 433 Md. 137, 70 A.3d 328 (2013)


Pharmaceutical Cases

Ambrosini v. Upjohn, 1995 WL 637650, at *4 (D.D.C. Oct. 18, 1995) (excluding plaintiff’s expert witness, Dr. Brian Strom, who was unable to state that mother’s use of Depo-Provero to prevent miscarriage more than doubled her child’s risk of a birth defect)

Ambrosini v. Labarraque, 101 F.3d 129, 135 (D.C. Cir. 1996)(Depo-Provera, birth defects) (testimony “does not warrant exclusion simply because it fails to establish the causal link to a specified degree of probability”)

Siharath v. Sandoz Pharms. Corp., 131 F. Supp. 2d 1347, 1356 (N.D. Ga. 2001)

Cloud v. Pfizer Inc., 198 F. Supp. 2d 1118, 1134 (D. Ariz. 2001) (sertraline and suicide)

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; “Court rejects Pfizer’s argument that unless Zoloft is shown to create a relative risk [of akathisia] greater than 2.0, [expert’s] testimony is inadmissible”), aff’d, 356 F. 3d 1326 (10th Cir.), cert. denied, 543 U.S. 917 (2004)

XYZ, et al. v. Schering Health Care Ltd., [2002] EWHC 1420, at ¶21, 70 BMLR 88 (QB 2002) (noting with approval that claimants had accepted the need to  prove relative risk greater than two; finding that most likely relative risk was 1.7, which required finding against claimants even if general causation were established)

Smith v. Wyeth-Ayerst Laboratories Co., 278 F. Supp. 2d 684, 691 (W.D.N.C. 2003) (recognizing that risk and cause are distinct concepts) (“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.”) (citing FJC Reference Manual at 384 – 85 (2d ed. 2000))

Kelley v. Sec’y of Health & Human Servs., 68 Fed. Cl. 84, 92 (Fed. Cl. 2005) (quoting Kelley v. Sec’y of Health & Human Servs., No. 02-223V, 2005 WL 1125671, at *5 (Fed. Cl. Mar. 17, 2005) (opinion of Special Master explaining that epidemiology must show relative risk greater than two to provide evidence of causation), rev’d on other grounds, 68 Fed. Cl. 84 (2005))

Pafford v. Secretary of HHS, No. 01–0165V, 64 Fed. Cl. 19, 2005 WL 4575936 at *8 (2005) (expressing preference for “an epidemiologic study demonstrating a relative risk greater than two … or dispositive clinical or pathological markers evidencing a direct causal relationship”) (citing Stevens v. Secretary of HHS, No.2001 WL 387418 at *12), aff’d, 451 F.3d 1352 (Fed. Cir. 2006)

Burton v. Wyeth-Ayerst Labs., 513 F. Supp. 2d 719, 730 (N.D. Tex. 2007) (affirming exclusion of expert witness testimony that did not meet Havner’s requirement of relative risks greater than two, Merrell Dow Pharm., Inc. v. Havner, 953 S.W.2d 706, 717–18 (Tex. 1997))

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 Bextra & Celebrex, 2008 N.Y. Misc. LEXIS 720, *23-24, 239 N.Y.L.J. 27 (2008) (“Proof that a relative risk is greater than 2.0 is arguably relevant to the issue of specific, as opposed to general causation and is not required for plaintiffs to meet their burden in opposing defendants’ motion.”)

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)

Vanderwerf v. SmithKlineBeecham Corp., 529 F.Supp. 2d 1294, 1302 n.10 (D. Kan. 2008), appeal dism’d, 603 F.3d 842 (10th Cir. 2010) (“relative risk of 2.00 means that a particular event of suicidal behavior has a 50 per cent chance that is associated with the exposure to Paxil … .”)

Wright v. American Home Products Corp., 557 F. Supp. 2d 1032, 1035-36 (W.D. Mo. 2008) (fenfluramine case)

Beylin v. Wyeth, 738 F.Supp. 2d 887, 893 n.3 (E.D.Ark. 2010) (MDL court) (Wilson, J. & Montgomery, J.) (addressing relative risk of two argument in dictum; holding that defendants’ argument that for an opinion to be relevant it must show that the medication causes the relative risk to exceed two “was without merit”)

Merck & Co. v. Garza, 347 S.W.3d 256 (Tex. 2011), rev’g 2008 WL 2037350, at *2 (Tex. App. — San Antonio May 14, 2008, no pet. h.)

Scharff v. Wyeth, No. 2:10–CV–220–WKW, 2012 WL 3149248, *6 & n.9, 11 (M.D. Ala. Aug. 1, 2012) (post-menopausal hormone therapy case; “A relative risk of 2.0 implies a 50% likelihood that an exposed individual’s disease was caused by the agent. The lower relative risk in this study reveals that some number less than half of the additional cases could be attributed to [estrogen and progestin].”)

Cheek v. Wyeth, LLC (In re Diet Drugs), 890 F.Supp. 2d 552 (E.D. Pa. 2012)


Medical Malpractice – Failure to Prescribe; Delay in Treatment

Merriam v. Wanger, 757 A.2d 778, 2000 Me. 159 (2000) (reversing judgment on jury verdict for plaintiff on grounds that plaintiff failed to show that defendant failure to act were, more likely than not, a cause of harm)

Bonesmo v. The Nemours Foundation, 253 F. Supp. 2d 801, 809 (D. Del. 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”)

Cottrelle v. Gerrard, 67 OR (3d) 737 (2003), 2003 CanLII 50091 (ONCA), at ¶ 25 (Sharpe, J.A.) (less than a probable chance that timely treatment would have made a difference for plaintiff is insufficient), leave to appeal den’d SCC (April 22, 2004)

Joshi v. Providence Health System of Oregon Corp., 342 Or. 152, 156, 149 P. 3d 1164, 1166 (2006) (affirming directed verdict for defendants when expert witness testified that he could not state, to a reasonable degree of medical probability, beyond 30%, that administering t-PA, or other anti-coagulant would have changed the outcome and prevented death)

Ensink v. Mecosta County Gen. Hosp., 262 Mich. App. 518, 687 N.W.2d 143 (Mich. App. 2004) (affirming summary judgment for hospital and physicians when patient could not greater than 50% probability of obtaining a better result had emergency physician administered t-PA within three hours of stroke symptoms)

Lake Cumberland, LLC v. Dishman, 2007 WL 1229432, *5 (Ky. Ct. App. 2007) (unpublished) confusing 30% with a “reasonable probability”; citing without critical discussion an apparently innumerate opinion of expert witness Dr. Lawson Bernstein)

Mich. Comp. Laws § 600.2912a(2) (2009) (“In an action alleging medical malpractice, the plaintiff has the burden of proving that he or she suffered an injury that more probably than not was proximately caused by the negligence of the defendant or defendants. In an action alleging medical malpractice, the plaintiff cannot recover for loss of an opportunity to survive or an opportunity to achieve a better result unless the opportunity was greater than 50%.”)

O’Neal v. St. John Hosp. & Med. Ctr., 487 Mich. 485, 791 N.W.2d 853 (Mich. 2010) (affirming denial of summary judgment when failure to administer therapy (not t-PA) in a timely fashion supposedly more than doubled the risk of stroke)

Kava v. Peters, 450 Fed. Appx. 470, 478-79 (6th Cir. 2011) (affirming summary judgment for defendants when plaintiffs expert witnesses failed to provide clear testimony that plaintiff specific condition would have been improved by timely administration of therapy)

Smith v. Bubak, 643 F.3d 1137, 1141–42 (8th Cir. 2011) (rejecting relative benefit testimony and suggesting in dictum that absolute benefit “is the measure of a drug’s overall effectiveness”)

Young v. Mem’l Hermann Hosp. Sys., 573 F.3d 233, 236 (5th Cir. 2009) (holding that Texas law requires a doubling of the relative risk of an adverse outcome to prove causation), cert. denied, ___ U.S. ___, 130 S.Ct. 1512 (2010)

Gyani v. Great Neck Medical Group, 2011 WL 1430037 (N.Y. S.Ct. for Nassau Cty., April 4, 2011) (denying summary judgment to medical malpractice defendant on stroke patient’s claims that failure to administer t-PA, on naked assertions of proximate cause by plaintiff’s expert witness, and without considering actual magnitude of risk increased by alleged failure to treat)

Samaan v. St. Joseph Hospital, 670 F.3d 21 (1st Cir. 2012)

Goodman v. Viljoen, 2011 ONSC 821 (CanLII)(treating a risk ratio of 1.7 for harm, or 0.6 for prevention, as satisfying the “balance of probabilities” when taken with additional unquantified, unvalidated speculation), aff’d, 2012 ONCA 896 (CanLII), leave appeal den’d, Supreme Court of Canada No. 35230 (July 11, 2013)

Briante v. Vancouver Island Health Authority, 2014 Brit. Columbia S.Ct 1511, at ¶ 317 (plaintiff must show “on a balance of probabilities that the defendant caused the injury”)


Toxic Tort Cases

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)

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.”)

Sanderson v. Internat’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)

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)

Schudel v. General Electric Co., 120 F.3d 991, 996 (9th Cir. 1997) (polychlorinated biphenyls)

Lofgren v. Motorola, 1998 WL 299925 *14 (Ariz. Super. June 1, 1998) (suggesting that relative risk requirement in tricholorethylene cancer medical monitoring case was arbitrary, but excluding plaintiffs’ expert witnesses on other grounds)

Berry v. CSX Transp., Inc., 709 So. 2d 552 (Fla. D. Ct.App. 1998) (reversing exclusion of plaintiff’s epidemiologist in case involving claims of toxic encephalopathy from solvent exposure, before Florida adopted Daubert standard)

Bartley v. Euclid, Inc., 158 F.3d 261 (5th Cir. 1998) (evidence at trial more than satisfied the relative risk greater than two requirement), rev’d on rehearing en banc, 180 F.3d 175 (5th Cir. 1999)

Magistrini v. One Hour Martinizing Dry Cleaning, 180 F. Supp. 2d 584, 591-92, 605 n.27, 606–07 (D.N.J. 2002) (“When the relative risk reaches 2.0, the risk has doubled, indicating that the risk is twice as high among the exposed group as compared to the non-exposed group. Thus, ‘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’.”) (quoting FJC Reference Manual at 384), aff’d, 68 F. App’x 356 (3d Cir. 2003)

Allison v. Fire Ins. Exchange, 98 S.W.3d 227, 239 (Tex. App. — Austin 2002, no pet. h.)

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 [1st Dist.] 2003) (affirming exclusion of expert witness testimony that did not meet Havner’s requirement of relative risks greater than two)

Exxon Corp. v. Makofski, 116 S.W.3d 176, 184-85 (Tex. App. — Houston 2003)

Frias v. Atlantic Richfield Co., 104 S.W.3d 925 (Tex. App. — Houston 2003)

Graham v. Lautrec, Ltd., 2003 WL 23512133, at *1 (Mich. Cir. Ct. 2003) (mold)

Mobil Oil Corp. v. Bailey, 187 S.W.3d 263, 268 (Tex. App. – Beaumont 2006) (affirming exclusion of expert witness testimony that did not meet Havner’s requirement of relative risks greater than two)

In re Lockheed Litig. Cases, 115 Cal. App. 4th 558 (2004)(alleging brain, liver, and kidney damage), rev’d in part, 23 Cal. Rptr. 3d 762, 765 (Cal. App. 2d Dist. 2005) (“[A] court cannot exclude an epidemiological study from consideration solely because the study shows a relative risk of less than 2.0.”), rev. dismissed, 192 P.3d 403 (Cal. 2007)

Novartis Grimsby Ltd. v. Cookson, [2007] EWCA (Civ) 1261, at para. 74 (causation was successfully established by risk ratio greater than two; per Lady Justice Smith: “Put in terms of risk, the occupational exposure had more than doubled the risk [of the bladder cancer complained of] due to smoking. . . . if the correct test for causation in a case such as this is the “but for” test and nothing less will do, that test is plainly satisfied on the facts as found. . . . In terms of risk, if the occupational exposure more than doubles the risk due to smoking, it must, as a matter of logic, be probable that the disease was caused by the former.”)

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.”)

King v. Burlington Northern Santa Fe Ry, 762 N.W.2d 24, 36-37 (Neb. 2009) (reversing exclusion of proffered testimony of Arthur Frank on claim that diesel exposure caused multiple myeloma, and addressing in dicta the ability of expert witnesses to speculate reasons why specific causation exists even with relative risk less than two) (“If a study shows a relative risk of 2.0, ‘the agent is responsible for an equal number of cases of disease as all other background causes.’ This finding ‘implies a 50% likelihood that an exposed individual’s disease was caused by the agent.’ If the relative risk is greater than 2.0, the study shows a greater than 50–percent likelihood that the agent caused the disease.”)(internal citations to Reference Manual on Scientific Evidence (2d ed. 2000) omitted)

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 is “contradictory and inconsistent”)

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

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

Blanchard v. Goodyear Tire & Rubber Co., No. 837-12-07 Wrcv (Eaton, J., June 28, 2010) (excluding expert witness, David Goldsmith, and entering summary judgment), aff’d, 190 Vt. 577, 30 A.3d 1271 (2011)

Pritchard v. Dow Agro Sciences, 705 F. Supp. 2d 471, 486 (W.D. Pa. 2010) (excluding opinions of Dr. Omalu on Dursban, in part because of low relative risk) (“Therefore, a relative risk of 2.0 is not dispositive of the reliability of an expert’s opinion relying on an epidemiological study, but it is a factor, among others, which the Court is to consider in its evaluation.”), aff’d, 430 Fed. Appx. 102, 2011 WL 2160456 (3d Cir. 2011)

Faust v. BNSF Ry., 337 S.W.3d 325, 337 (Tex. Ct. App. 2d Dist. 2011) (“To be considered reliable scientific evidence of general causation, an epidemiological study must (1) have a relative risk of 2.0 and (2) be statistically significant at the 95% confidence level.”) (internal citations omitted)

Nonnon v. City of New York, 88 A.D.3d 384, 398-99, 932 N.Y.S.2d 428, 437-38 (1st Dep’t 2011) (holding that the strength of the epidemiologic evidence, with relative risks greater than 2.0, permitted an inference of causation)

Milward v. Acuity Specialty Products Group, Inc., 969 F. Supp. 2d 101, 112-13 & n.7 (D. Mass. 2013) (avoiding doubling of risk issue and holding that plaintiffs’ expert witnesses failed to rely upon a valid exposure estimate and lacked sufficient qualifications to evaluate and weigh the epidemiologic studies that provided estimates of relative risk) (generalities about the “core competencies” of physicians or specialty practices cannot overcome an expert witness’s explicit admission of lacking the epidemiologic expertise needed to evaluate and weigh the epidemiologic studies and methods at issue in the case. Without the requisite qualifications, an expert witness cannot show that the challenged opinion has a sufficiently reliable scientific foundation in epidemiologic studies and method.)

Berg v. Johnson & Johnson, 940 F.Supp.2d 983 (D.S.D. 2013) (talc and ovarian cancer)


Other

In re Hannaford Bros. Co. Customer Data Sec. Breach Litig., 293 F.R.D. 21, 2:08-MD-1954-DBH, 2013 WL 1182733, *1 (D. Me. Mar. 20, 2013) (Hornby, J.) (denying motion for class certification) (“population-based probability estimates do not speak to a probability of causation in any one case; the estimate of relative risk is a property of the studied population, not of an individual’s case.”)

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