TORTINI

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ALI Reporters Are Snookered by Racette Fallacy

April 27th, 2015

In the Reference Manual on Scientific Evidence, the authors of the epidemiology chapter advance instances of acceleration of onset of disease as an example of a situation in which reliance upon doubling of risk will not provide a reliable probability of causation calculation[1]. In a previous post, I suggested that the authors’ assertion may be unfounded. SeeReference Manual on Scientific Evidence on Relative Risk Greater Than Two For Specific Causation Inference” (April 25, 2014). Several epidemiologic methods would permit the calculation of relative risk within specific time windows from first exposure.

The American Law Institute (ALI) Reporters, for the Restatement of Torts, make similar claims.[2] First, the Reporters, citing the Manual’s second edition, repeat the Manual’s claim that:

 “Epidemiologists, however, do not seek to understand causation at the individual level and do not use incidence rates in group to studies to determine the cause of an individual’s disease.”

American Law Institute, Restatement (Third) of Torts: Liability for Physical and Emotional Harm § 28(a) cmt. b(4) & rptrs. notes (2010) [Comment b(4)]. In making this claim, the Reporters ignore an extensive body of epidemiologic studies on genetic associations and on biomarkers, which do address causation implicitly or explicitly, on an individual level.

The Reporters also repeat the Manual’s doubtful claim that acceleration of onset of disease prevents an assessment of attributable risk, although they acknowledge that an average earlier age of onset would form the basis of damages calculations rather than calculations for damages for an injury that would not have occurred but for the tortious exposure. Comment b(4). The Reporters go a step further than the Manual, however, and provide an example of the acceleration-of-onset studies that they have in mind:

“For studies whose results suggest acceleration, see Brad A. Racette, Welding-Related Parkinsonism: Clinical Features, Treatments, and Pathophysiology,” 56 Neurology 8, 12 (2001) (stating that authors “believe that welding acts as an accelerant to cause [Parkinson’s Disease]… .”

The citation to Racette’s 2001 paper[3] is curious, interesting, disturbing, and perhaps revealing. In this 2001 paper, Racette misrepresented the type of study he claimed to have done, and the inferences he drew from his case series are invalid. Any one experienced in the field of epidemiology would have dismissed this study, its conclusions, and its suggested relation between welding and parkinsonism.

Dr. Brad A. Racette teaches and practices neurology at Washington University in St. Louis, across the river from a hotbed of mass tort litigation, Madison County, Illinois. In the 1990s, Racette received referrals from plaintiffs’ attorneys to evaluate their clients in litigation over exposure to welding fumes. Plaintiffs were claiming that their occupational exposures caused them to develop manganism, a distinctive parkinsonism that differs from Parkinson’s disease [PD], but has signs and symptoms that might be confused with PD by unsophisticated physicians unfamiliar with both manganism and PD.

After the publication of his 2001 paper, Racette became the darling of felon Dicky Scruggs and other plaintiffs’ lawyers. The litigation industrialists invited Racette and his team down to Alabama and Mississippi, to conduct screenings of welding tradesmen, recruited by Scruggs and his team, for potential lawsuits for PD and parkinsonism. The result was a paper that helped Scruggs propel a litigation assault against the welding industry.[4]

Racette’s 2001 paper was accompanied by a press release, as have many of his papers, in which he was quoted as stating that “[m]anganism is a very different disease” from PD. Gila Reckess, “Welding, Parkinson’s link suspected” (Feb. 9, 2001)[5].

Racette’s 2001 paper provoked a strongly worded letter that called Racette and his colleagues out for misrepresenting the nature of their work:

“The authors describe their work as a case–control study. Racette et al. ascertained welders with parkinsonism and compared their concurrent clinical features to those of subjects with PD. This is more consistent with a cross-sectional design, as the disease state and factors of interest were ascertained simultaneously. Cross-sectional studies are descriptive and therefore cannot be used to infer causation.”

*****

“The data reported by Racette et al. do not necessarily support any inference about welding as a risk factor in PD. A cohort study would be the best way to evaluate the role of welding in PD.”

Bernard Ravina, Andrew Siderowf, John Farrar, Howard Hurtig, “Welding-related parkinsonism: Clinical features, treatment, and pathophysiology,” 57 Neurology 936, 936 (2001).

As we will see, Dr. Ravina and his colleagues were charitable to suggest that the study was more compatible with a cross-sectional study. Racette had set out to determine “whether welding-related parkinsonism differs from idiopathic PD.” He claimed that he had “performed a case-control study,” with a case group of welders and two control groups. His inferences drawn from his “data” are, however, fallacious because he employed an invalid study design.

In reality, Racette’s paper was nothing more than a chart review, a case series of 15 “welders” in the context of a movement disorder clinic. After his clinical and radiographic evaluation, Racette found that these 15 cases were clinically indistinguishable from PD, and thus unlike manganism. Racette did not reveal whether any of these 15 welders had been referred by plaintiffs’ counsel; nor did he suggest that these welding tradesmen made up a disproportionate number of his patient base in St. Louis, Missouri.

Racette compared his selected 15 career welders with PD to his general movement disorders clinic patient population, for comparison. From the patient population, Racette deployed two “control” groups, one matched for age and sex with the 15 welders, and the other group not matched. The America Law Institute reporters are indeed correct that Racette suggested that the average age of onset for these 15 welders was lower than that for his non-welder patients, but their uncritical embraced overlooked the fact that Racette’s suggestion does not support his claimed inference that in welders, therefore, “welding exposure acts as an accelerant to cause PD.”

Racette’s claimed inference is remarkable because he did not perform an analytical epidemiologic study that was capable of generating causal inferences. His paper incongruously presents odds ratios, although the controls have PD, the disease of interest, which invalidates any analytical inference from his case series. Given the referral and selection biases inherent in tertiary-care specialty practices, this paper can provide no reliable inferences about associations or differences in ages of onset. Even within the confines of a case series misrepresented to be a case-control study, Racette acknowledged that “[s]ubsequent comparisons of the welders with age-matched controls showed no significant differences.”

NOT A CASE-CONTROL STUDY

That Racette wrongly identified his paper as a case-control study is beyond debate. How the journal Neurology accepted the paper for publication is a mystery. The acceptance of the inference by the ALI Reporter, lawyers and judges, is regrettable.

Structurally, Racette’s paper could never quality as a case-control study, or any other analytical epidemiologic study. Here is how a leading textbook on case-control studies defines a case-control study:

“In a case-control study, individuals with a particular condition or disease (the cases) are selected for comparison with a series of individuals in whom the condition or disease is absent (the controls).”

James J. Schlesselman, Case-control Studies. Design, Conduct, Analysis at 14 (N.Y. 1982)[6].

Every patient in Racette’s paper, welders and non-welders, have the outcome of interest, PD. There is no epidemiologic study design that corresponds to what Racette did, and there is now way to draw any useful inference from Racette’s comparisons. Racette’s paper violates the key principle for a proper case-control study; namely, all subjects must be selected independently of the study exposure that is under investigation. Schlesselman stressed that that identifying an eligible case or control must not depend upon that person’s exposure status for any factor under consideration. Id. Racette’s 2001 paper deliberately violated this basic principle.

Racette’s study design, with only cases with the outcome of interest appearing in the analysis, recklessly obscures the underlying association between the exposure (welding) and age in the population. We would, of course, expect self-identified welders to be younger than the average Parkinson’s disease patient because welding is physical work that requires good health. An equally fallacious study could be cobbled together to “show” that the age-of-onset of Parkinson’s disease for sitcom actors (such as Michael J. Fox) is lower than the age-of-onset of Parkinson’s disease for Popes (such as John Paul II). Sitcom actors are generally younger as a group than Popes. Comparing age of onset between disparate groups that have different age distributions generates a biased comparison and an erroneous inference.

The invalidity and fallaciousness of Racette’s approach to studying the age-of-onset issue of PD in welders, and his uncritical inferences, have been extensively commented upon in the general epidemiologic literature. For instance, in studies that compared the age at death for left-handed versus right-handed person, studies reported an observed nine-year earlier death for left handers, leading to (unfounded) speculation that earlier mortality resulted from birth and life stressors and accidents for left handers, living in a world designed to accommodate right-handed person[7]. The inference has been shown to be fallacious and the result of social pressure in the early twentieth century to push left handers to use their right hands, a prejudicial practice that abated over the decades of the last century. Left handers born later in the century were less likely to be “switched,” as opposed to those persons born earlier and now dying, who were less likely to be classified as left-handed, as a result of a birth-cohort effect[8]. When proper prospective cohort studies were conducted, valid data showed that left-handers and right-handers have equivalent mortality rates[9].

Epidemiologist Ken Rothman addressed the fallacy of Racette’s paper at some length in one of his books:

“Suppose we study two groups of people and look at the average age at death among those who die. In group A, the average age of death is 4 years; in group B, it is 28 years. Can we say that being a member of group A is riskier than being a member of group B? We cannot… . Suppose that group A comprises nursery school students and group B comprises military commandos. It would be no surprise that the average age at death of people who are currently military commandos is 28 years or that the average age of people who are currently nursery students is 4 years. …

In a study of factory workers, an investigator inferred that the factory work was dangerous because the average age of onset of a particular kind of cancer was lower in these workers than among the general population. But just as for the nursery school students and military commandos, if these workers were young, the cancers that occurred among them would have to be occurring in young people. Furthermore, the age of onset of a disease does not take into account what proportion of people get the disease.

These examples reflect the fallacy of comparing the average age at which death or disease strikes rather than comparing the risk of death between groups of the same age.”

Kenneth J. Rothman, “Introduction to Epidemiologic Thinking,” in Epidemiology: An Introduction at 5-6 (N.Y. 2002).

And here is how another author of Modern Epidemiology[10] addressed the Racette fallacy in a different context involving PD:

“Valid studies of age-at-onset require no underlying association between the risk factor and aging or birth cohort in the source population. They must also consider whether a sufficient induction time has passed for the risk factor to have an effect. When these criteria and others cannot be satisfied, age-specific or standardized risks or rates, or a population-based case-control design, must be used to study the association between the risk factor and outcome. These designs allow the investigator to disaggregate the relation between aging and the prevalence of the risk factor, using familiar methods to control confounding in the design or analysis. When prior knowledge strongly suggests that the prevalence of the risk factor changes with age in the source population, case-only studies may support a relation between the risk factor and age-at-onset, regardless of whether the inference is justified.”

Jemma B. Wilk & Timothy L. Lash, “Risk factor studies of age-at-onset in a sample ascertained for Parkinson disease affected sibling pairs: a cautionary tale,” 4 Emerging Themes in Epidemiology 1 (2007) (internal citations omitted) (emphasis added).

A properly designed epidemiologic study would have avoided Racette’s fallacy. A relevant cohort study would have enrolled welders in the study at the outset of their careers, and would have continued to follow them even if they changed occupations. A case-control study would have enrolled cases with PD and controls without PD (or more broadly, parkinsonism), with cases and controls selected independently of their exposure to welding fumes. Either method would have determined the rate of PD in both groups, absolutely or relatively. Racette’s paper, which completely lacked non-PD cases, could not have possibly accomplished his stated objectives, and it did not support his claims.

Racette’s questionable work provoked a mass tort litigation and ultimately federal Multi-District Litigation 1535.[11] Ultimately, analytical epidemiologic studies consistently showed no association between welding and PD. A meta-analysis published in 2012 ended the debate[12] as a practical matter, and MDL 1535 is no more. How strange that the ALI reporters chose the Racette work as an example of their claims about acceleration of onset!


[1] Michael D. Green, D. Michal Freedman, and Leon Gordis, “Reference Guide on Epidemiology,” in Federal Judicial Center, Reference Manual on Scientific Evidence 549, 614 (Wash., DC 3d ed. 2011).

[2] Michael D. Green was an ALI Reporter, and of course, an author of the chapter in the Reference Manual.

[3] Brad A. Racette, L. McGee-Minnich, S. M. Moerlein, J. W. Mink, T. O. Videen, and Joel S. Perlmutter, “Welding-related parkinsonism: clinical features, treatment, and pathophysiology,” 56 Neurology 8 (2001).

[4] See Brad A. Racette, S.D. Tabbal, D. Jennings, L. Good, Joel S. Perlmutter, and Brad Evanoff, “Prevalence of parkinsonism and relationship to exposure in a large sample of Alabama welders,” 64 Neurology 230 (2005); Brad A. Racette, et al., “A rapid method for mass screening for parkinsonism,” 27 Neurotoxicology 357 (2006) (duplicate publication of the earlier, 2005, paper).

[5] Previously available at <http://record.wustl.edu/archive/2001/02-09-01/articles/welding.html>, last visited on June 27, 2005.

 

[6] See also Brian MacMahon & Dimitrios Trichopoulos, Epidemiology. Principles and Methods at 229 (2ed 1996) (“A case-control study is an inquiry in which groups of individuals are selected based on whether they do (the cases) or do not (the controls) have the disease of which the etiology is to be studied.”); Jennifer L. Kelsey, W.D. Thompson, A.S. Evans, Methods in Observational Epidemiology at 148 (N.Y. 1986) (“In a case-control study, persons with a given disease (the cases) and persons without the disease (the controls) are selected … .”).

[7] See, e.g., Diane F. Halpern & Stanley Coren, “Do right-handers live longer?” 333 Nature 213 (1988); Diane F. Halpern & Stanley Coren, “Handedness and life span,” 324 New Engl. J. Med. 998 (1991).

[8] Kenneth J. Rothman, “Left-handedness and life expectancy,” 325 New Engl. J. Med. 1041 (1991) (pointing out that by comparing age of onset method, nursery education would be found more dangerous than paratrooper training, given that the age at death of pres-schoolers wo died would be much lower than that of paratroopers who died); see also Martin Bland & Doug Altman, “Do the left-handed die young?” Significance 166 (Dec. 2005).

[9] See Philip A. Wolf, Ralph B. D’Agostino, Janet L. Cobb, “Left-handedness and life expectancy,” 325 New Engl. J. Med. 1042 (1991); Marcel E. Salive, Jack M. Guralnik & Robert J. Glynn, “Left-handedness and mortality,” 83 Am. J. Public Health 265 (1993); Olga Basso, Jørn Olsen, Niels Holm, Axel Skytthe, James W. Vaupel, and Kaare Christensen, “Handedness and mortality: A follow-up study of Danish twins born between 1900 and 1910,” 11 Epidemiology 576 (2000). See also Martin Wolkewitz, Arthur Allignol, Martin Schumacher, and Jan Beyersmann, “Two Pitfalls in Survival Analyses of Time-Dependent Exposure: A Case Study in a Cohort of Oscar Nominees,” 64 Am. Statistician 205 (2010); Michael F. Picco, Steven Goodman, James Reed, and Theodore M. Bayless, “Methodologic pitfalls in the determination of genetic anticipation: the case of Crohn’s disease,” 134 Ann. Intern. Med. 1124 (2001).

[10] Kenneth J. Rothman, Sander Greenland, Timothy L. Lash, eds., Modern Epidemiology (3d ed. 2008).

[11] Dicky Scruggs served on the Plaintiffs’ Steering Committee until his conviction on criminal charges.

[12] James Mortimer, Amy Borenstein, and Lorene Nelson, “Associations of welding and manganese exposure with Parkinson disease: Review and meta-analysis,” 79 Neurology 1174 (2012).

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

April 25th, 2015

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].”)


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)

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.)

Adverse Liver Events and Causal Claims Against Black Cohosh

April 6th, 2015

Liver toxicity in pharmaceutical products liability cases is one of the more difficult categories of cases for judicial gatekeeping because of the possibility of idiosyncratic liver toxicity. Sometimes a plaintiff will exploit this difficulty and try to recover for an acute liver reaction.

Susan Grant began to take a black cohosh herbal remedy in 2002, and within a year, developed autoimmune hepatitis, which required her to undergo a liver transplant. She and her husband sued the seller of black cohosh for substantial damages. Grant v. Pharmavite, LLC, 452 F. Supp 2d 903 (D. Neb. 2006). Granted enlisted two expert witnesses, Michael Corbett, Ph.D, a toxicologist, and her treating gastroenterologist, Michael Sorrell, M.D. The defense relying upon liver expert, Phillip Guzelian, M.D., challenged the admissibility of plaintiffs’ expert witnesses’ opinions under the federal rules.

Struggling with the law, Senior Judge Strom observed that Nebraska law requires expert witness opinion testimony on causation. Id. at 906. Of course, in this diversity action, federal law controlled on the scope and the requirements of expert witness opinion testimony.

And in a similarly offbeat way, Judge Strom suggested that plaintiffs’ expert witnesses need not have opinion supported by evidence:

While it is not necessary that an opinion be backed by scientific research, it is necessary that an expert’s testimony, which contradicts all of the research, at minimum address and distinguish the contradictory research in order to support the expressed opinion.”

Id. at 907 (emphasis added). Senior Judge Strom thus suggests had there been no published research at all, then Dr. Corbett could just make up an opinion, not backed by scientific research. This is, of course, seriously wrong, but fortunately it amounts only to obiter detritus, because Judge Strom believed that given the available studies, the testifying expert witnesses had to do more than simply criticize the studies that disagreed with their subjective opinion.

Michael Corbett, Ph.D, a consultant in “chemical toxicology,” from Omaha, Nebraska, criticized existent studies, which generally failed to identify liver toxicity, but he failed to conduct his own studies. Id. at 907. And Corbett also failed to explain why he rejected the great weight of medical publications that found that black cohosh was not hepatotoxic. Id. Michael Sorrell, M.D., started out as Ms. Grant’s treating gastroenterologist, but became a litigation expert witness. He was generally unaware of the randomized clinical trials of black cohosh, or any study that, or group of scientists who, supported his opinion. Id. at 909.

To Dr. Sorrell’s credit, he did attempt to write up a case report, which was published after the termination of the case. Unfortunately for Dr. Sorrell and his colleagues, Ms. Grant and her lawyers were less than forthcoming about her medical history, which included medications and lifestyle variables that were apparently not shared with Dr. Sorrell. Id. at 909.

You know that the quality of gatekeeping due process is strained when judges fail to cite key studies sufficiently to permit their readers to find the scientific evidence. Between Google Scholar and PubMed, however, you can find Dr. Sorrell’s case report, which was published in 2005, before Judge Strom issued his Rule 702 opinion. Josh Levitsky, Tyron A. Alli, James Wisecarver, and Michael F. Sorrell, “Fulminant liver failure associated with the use of black cohosh,” 50 Digestive Dis. Sci. 538 (2005). If nothing else, Judge Strom provoked an erratum from Dr. Sorrell and colleagues:

“After the article was published, it was brought to the authors’ attention through legal documentation and testimony that the patient admitted to consuming alcohol and had been taking other medications at the time of her initial presentation of liver failure. From these records, she reported drinking no more than six glasses of wine per week. In addition, up until presentation, she was taking valacyclovir 500 mg daily for herpes prophylaxis for 2 years, an occasional pseudoephedrine tablet, calcium carbonate 500 mg three times daily, iron sulfate 325 mg daily and ibuprofen up to three times weekly. She had been taking erythromycin tablets but discontinued those 3 months prior to presentation.

The authors regret the omission of this information from the original case report. While this new information is important to include as a correction to the history, it does not change the authors’ clinical opinion … .”

The erratum omits that Ms. Grant was taking Advil (ibuprofen) at the time of her transplantation, and that she had been taking erythromycin for 2.5 years, stopping just a few months before her acute liver illness. The Valtrex use shows that Ms. Grant had a chronic herpes infection. In the past, plaintiff took such excessive doses of ibuprofen that she developed anemia. Grant v. Pharmavite, LLC, 452 F. Supp 2d at 909 n.1. Hardly an uncomplicated case report to interpret for causality and an interesting case history of confirmation bias. Remarkably, the journal charges $39.95 to download the erratum, as much as the case report itself!

And how has the plaintiff’s claim fared in the face of the evolving scientific record since Judge Strom’s opinion?

Not well.

See, e.g., Peter W Whiting, Andrew Clouston and Paul Kerlin, “Black cohosh and other herbal remedies associated with acute hepatitis,” 177 Med. J. Australia 432 (2002); Cohen SM, O’Connor AM, Hart J, et al. Autoimmune hepatitis associated with the use of black cohosh: a case study. 11 Menopause 575 (2004); Christopher R. Lynch, Milan E. Folkers, and William R. Hutson, “Fulminant hepatic failure associated with the use of black cohosh: A case report,” 12 Liver Transplantation 989 (2006); Elizabeth C-Y Chow, Marcus Teo, John A Ring and John W Chen, “Liver failure associated with the use of black cohosh for menopausal symptoms,” 188 Med. J. Australia 420 (2008); Gail B. Mahady, Tieraona Low Dog, Marilyn L. Barrett, Mary L. Chavez, Paula Gardiner, Richard Ko, Robin J. Marles, Linda S. Pellicore, Gabriel I. Giancaspro, and Dandapantula N. Sarma, “United States Pharmacopeia review of the black cohosh case reports of hepatotoxicity,” 15 Menopause 628 (2008) (toxicity only possible on available evidence); D. Joy, J. Joy, and P. Duane, “Black cohosh: a cause of abnormal postmenopausal liver function tests,” 11 Climacteric 84 (2008); Lily Dara, Jennifer Hewett, and Joseph Kartaik Lim, “Hydroxycut hepatotoxicity: A case series and review of liver toxicity from herbal weight loss supplements,” 14 World J. Gastroenterol. 6999 (2008); F. Borrelli & E. Ernst, “Black cohosh (Cimicifuga racemosa): a systematic review of adverse events,” Am. J. Obstet. & Gyn. 455 (2008); Rolf Teschke & A. Schwarzenboeck, “Suspected hepatotoxicity by Cimicifugae racemosae rhizoma (black cohosh, root): critical analysis and structured causality assessment,” 16 Phytomedicine 72 (2009); Stacie E. Geller, Lee P. Shulman, Richard B. van Breemen, Suzanne Banuvar, Ying Zhou, Geena Epstein, Samad Hedayat, Dejan Nikolic, Elizabeth C. Krause, Colleen E. Piersen, Judy L. Bolton, Guido F. Pauli, and Norman R. Farnsworth, “Safety and Efficacy of Black Cohosh and Red Clover for the Management of Vasomotor Symptoms: A Randomized Controlled Trial,” 16 Menopause 1156 (2009) (89 women randomized to four groups; no hepatic events in trial not powered to detect them); Rolf Teschke, “Black cohosh and suspected hepatotoxicity: inconsistencies, confounding variables, and prospective use of a diagnostic causality algorithm. A critical review,” 17 Menopause 426 (2010) (“The presented data do not support the concept of hepatotoxicity in a primarily suspected causal relationship to the use of BC and failure to provide a signal of safety concern, but further efforts have to be undertaken to dismiss or to substantiate the existence of BC hepatotoxicity as a special disease entity. The future strategy should be focused on prospective causality evaluations in patients diagnosed with suspected BC hepatotoxicity, using a structured, quantitative, and hepatotoxicity-specific causality assessment method.”); Fabio Firenzuoli, Luigi Gori, and Paolo Roberti di Sarsina, “Black Cohosh Hepatic Safety: Follow-Up of 107 Patients Consuming a Special Cimicifuga racemosa rhizome Herbal Extract and Review of Literature,” 2011 Evidence-Based Complementary & Alternative Med. 1 (2011); Rolf Teschke, Wolfgang Schmidt-Taenzer and Albrecht Wolff, “Spontaneous reports of assumed herbal hepatotoxicity by black cohosh: is the liver-unspecific Naranjo scale precise enough to ascertain causality?” 20 Pharmacoepidemiol. & Drug Safety 567 (2011) (causation unlikely or excluded); Rolf Teschke, Alexander Schwarzenboeck, Wolfgang Schmidt-Taenzer, Albrecht Wolff, and Karl-Heinz Hennermann, “Herb induced liver injury presumably caused by black cohosh: A survey of initially purported cases and herbal quality specifications,” 11 Ann. Hepatology 249 (2011).

Cherry Picking; Systematic Reviews; Weight of the Evidence

April 5th, 2015

In a paper prepared for one of Professor Margaret Berger’s symposia on law and science, Lisa Bero, a professor of clinical pharmacy in the University of California San Francisco’s School of Pharmacy identified a major source of error in published reviews of putative health effects:

“The biased citation of studies in a review can be a major source of error in the results of the review. Authors of reviews can influence their conclusions by citing only studies that support their preconceived, desired outcome.”

Lisa Bero, “Evaluating Systematic Reviews and Meta-Analyses,” 14 J. L. & Policy 569, 576 (2006). Biased citation, consideration, and reliance are major sources of methodological error in courtroom proceedings as well. Sometimes astute judges recognize and bar expert witnesses who would pass off their opinions, as well considered, when they are propped up only by biased citation. Unfortunately, courts have been inconsistent, sometimes rewarding cherry picking of studies by admitting biased opinions[1], sometimes unhorsing the would-be expert witnesses by excluding their opinions[2].

Given that cherry picking or “biased citation” is recognized in the professional community as a rather serious methodological sin, judges may be astonished to learn that both phrases, “cherry picking” and “biased citation” do not appear in the third edition of the Reference Manual on Scientific Evidence. Of course, the Manual could have dealt with the underlying issue of biased citation by affirmatively promoting the procedure of systematic reviews, but here again, the Manual falls short. There is no discussion of systematic review in the chapters on toxicology[3], epidemiology[4], or statistics[5]. Only the chapter on clinical medicine discusses the systematic review, briefly[6]. The absence of support for the procedures of systematic reviews, combined with the occasional cheerleading for “weight of the evidence,” in which expert witnesses subjectively include and weight studies to reach pre-ordained opinions, tends to undermines the reliability of the latest edition of the Manual[7].


[1] Spray-Rite Serv. Corp. v. Monsanto Co., 684 F.2d 1226, 1242 (7th Cir. 1982) (failure to consider factors identified by opposing side’s expert did not make testimony inadmissible).

[2] In re Zoloft, 26 F. Supp. 3d 449 (E.D. Pa. 2014) (excluding perinatal epidemiologist, Anick Bérard, for biased cherry picking of data points); In re Accutane, No. 271(MCL), 2015 WL 753674, 2015 BL 59277 (N.J.Super. Law Div. Atlantic Cty. Feb. 20, 2015) (excluding opinions Drs. Arthur Kornbluth and David Madigan because of their authors’ unjustified dismissal of studies that contradicted or undermined their opinions); In re Bextra & Celebrex Mktg. Sales Practices & Prods. Liab. Litig., 524 F.Supp. 2d 1166, 1175–76, 1179 (N.D.Cal.2007) (holding that expert witnesses may not ‘‘cherry-pick[ ]’’ observational studies to support a conclusion that is contradicted by randomized controlled trials, meta-analyses of such trials, and meta-analyses of observational studies; excluding expert witness who ‘‘ignores the vast majority of the evidence in favor of the few studies that support her conclusion’’); Grant v. Pharmative, LLC, 452 F. Supp. 2d 903, 908 (D. Neb. 2006) (excluding expert witness opinion testimony that plaintiff’s use of black cohash caused her autoimmune hepatitis) (“Dr. Corbett’s failure to adequately address the body of contrary epidemiological evidence weighs heavily against admission of his testimony.”); Downs v. Perstorp Components, Inc., 126 F. Supp. 2d 1090,1124-29 (E.D. Tenn. 1999) (expert’s opinion raised seven “red flags” indicating that his testimony was litigation biased), aff’d, 2002 U.S. App. Lexis 382 (6th Cir. Jan. 4, 2002).

[3] Bernard D. Goldstein & Mary Sue Henifin, “Reference Guide on Toxicology,” in Reference Manual on Scientific Evidence 633 (3d ed. 2011).

[4] Michael D. Green, D. Michal Freedman, and Leon Gordis, “Reference Guide on Epidemiology,” in Reference Manual on Scientific Evidence 549 (3d ed. 2011).

[5] David H. Kaye & David A. Freedman, “Reference Guide on Statistics,” in Reference Manual on Scientific Evidence 209 (3d ed. 2011).

[6] John B. Wong, Lawrence O. Gostin, and Oscar A. Cabrera, “Reference Guide on Medical Testimony,” in Federal Judicial Center and National Research Council, Reference Manual on Scientific Evidence 687 (3d ed. 2011).

[7] See Margaret A. Berger, “The Admissibility of Expert Testimony,” in Reference Manual on Scientific Evidence 11, 20 & n.51 (3d ed. 2011) (posthumously citing Milward v. Acuity Specialty Products Group, Inc., 639 F.3d 11, 26 (1st Cir. 2011), with approval, for reversing exclusion of expert witnesses who advanced “weight of the evidence” opinions).

The opinions, statements, and asseverations expressed on Tortini are my own, or those of invited guests, and these writings do not necessarily represent the views of clients, friends, or family, even when supported by good and sufficient reason.