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. See “Reference 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. c(4) & rptrs. notes (2010) [Comment c(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 c(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 embrace 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 no 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).
