Perhaps the most important point of this law review article, “Differential Etiology: Inferring Specific Causation in the Law from Group Data in Science,” is that general causation is necessary but insufficient, standing alone, to show specific causation. To be sure, the authors proclaimed that strong evidence of general causation somehow reduces the burden to show specific causation, but this pronouncement turned out to be an ipse dixit, without supporting analysis or citation. On general causation itself, what the authors characterized as the “ruling in” part of differential etiology, the authors offered some important considerations for courts to consider. Not the least of the important advice on general causation was urging caution in interpreting results when “strength of a relationship is modest.”[1] Given that they were talking to judges and lawyers, the advice might have taken on greater saliency if the authors explicitly noted that modest strength of a putative relationship means small relative risks, such as those smaller than two or three.
Acute Onset Conditions
The authors’ stated goal of bringing clarity to the determination of differential-etiology is a laudable one. In seeking clarity, they brush away some “easy” cases, such as the causal determination of acute onset conditions. Even so, the authors do not give any concrete examples. A broken bone discovered immediately after a car crash would hardly give a court much pause, but something such as the onset of acute liver failure shortly after ingesting a new medication turns out to be much more complicated than many would anticipate. Viral infections and autoimmune disease must be eliminated, and so such events are clearly in the realm of differential etiology, despite the close temporal proximity.
So-Called Signature Diseases
The authors also try to brush aside the “easy” case of signature diseases as not requiring differential etiology. The complexity of such cases ultimately embarrasses everyone. The authors no doubt thought that they were on safe ground in proffering the example of mesothelioma as a signature cancer caused by only asbestos (without wading into the deeper complexity of what is asbestos and which minerals in what mineralogical habit actually cause the disease).[2] Unfortunately, mesothelioma has never been a truly signal disease. The authors nonetheless consider it as one, with the caveat that mesotheliomas not caused by asbestos are “very rare.” And what was the authority for this statement? The Pennsylvania Supreme Court! Now the Pennsylvania Supreme Court is no doubt, at times, an authority on Pennsylvania law, if only because the Court is the last word on this contorted body of law. The Justices of that Court, however, would probably be the first to disclaim any credibility on the causes of any disease.[3]
The authors further distort the notion of signature diseases by stating that “[v]aginal adenocarcinoma in young women appears to be a signature disease associated with maternal use of DES.”[4] This cannot be right because over 10% of vaginal cancers are adenocarcimas. The principle of charity requires us to assume that the authors meant to indicate clear cell vaginal adenocarcinoma, but even so, charity will not correct the mistake. DES daughters do indeed have an increased risk of developing developing clear cell adenocarcinoma, but this type of cancer was well described before DES was ever invented and prescribed to women.[5]
Perhaps the safest ground for signature diseases is in microbiology, where we have infectious disease defined by the microbial agent that is uniquely associated with the disease. Probably close to the infectious diseases are the nutritional deficiency diseases defined by the absence of an essential nutrient or vitamin. To be sure, there are non-infectious diseases such as the pneumoconioses, each defined by the nature of the inhaled particle. Contrary to the authors’ contention, these diseases no not necessarily remove differential etiology from the analysis. Silicosis has a distinctive radiographic appearance, and yet that radiographic appearance is the same in many cases of coccidioidomycosis (Valley Fever). Asbestosis has a different radiographic appearance of the lungs and pleura, but the radiographic patterns might well be confused with the sequelae of rheumatoid arthritis or other interstitial lung diseases. At low levels of profusion of radiographic opacities, diseases such asbestosis and silicosis have diagnostic criteria that are far from perfect sensitivity and specificity. In one of the very first asbestos cases I defended, the claimant was diagnosed, by no less than the late Dr. Irving Selikoff,[6] with asbestosis, 3/3 on the ILO scale of linear, irregular radiographic lung opacities. An autopsy, however, found that there was no asbestosis at all, or even an elevated tissue fiber burden; the claimant had died of bilateral lymphangenitic carcinomatosis.
Definitive Mechanistic Pathway to Individual Causation
The paper presents a limited discussion of genetic causation. In the instance of mutations of highly penetrant alleles, identifying the genetic mutation will provide the general and the specific cause in a case. The authors also acknowledge that there may be cases involving hypothetical biomarkers that reveals a well-documented causal pathway from exposure to disease.
Differential Etiologies
So what happens when the plaintiff is claiming that he has developed a disease of ordinary life, one that has multiple known causes? Disease onset is not acute, but rather after a lengthy latency period. The plaintiff wants to inculpate the supposedly tortious exposure (the tortogen), and avoid the conclusion that any or all of the known alternative causes participated in his case. If there are cases of the disease without known causes (idiopathogens), the claimant will need to exclude idiopathogens in favor of fingering the tortogen as responsible for his bad outcome.
The authors helpfully distinguish differential diagnosis from differential etiology. The confusion of the two concepts has led to courts’ generally over-endorsing the black box of clinical judgment in health effects litigation. At the very least, this article can perhaps help the judiciary to move on from this naïve confusion.[7]
The authors advance the vague notion that somehow “clinical information” can supplement a relative that is not greater than two to augment the specific causation inference. This was, to be sure, the assertion of the New Jersey Supreme Court, based upon the improvident concession of the defense lawyer who argued the case.[8] There was nothing in the record of the New Jersey case, however, that would support the relevance of clinical information to the causal analysis of the plaintiff’s colorectal cancer.
The authors also point to a talc ovarian cancer case as exemplifying the use of clinical data to supplement a relative risk below two.[9] The cited case, however, involved expert witnesses who claimed a relative risk greater than two for the tortogen, and who failed to show how clinical information (such as the presence of talc in ovarian tissue) made the claimant any more likely to have had a cancer caused by talc.
Adverting to “clinical information” to supplement the relative risk all-too-often is hand waving that offers no analytical support for the specific causal inference. The clinical factors often are covariates in the multivariate model that generated the relevant relative risk. As such, the relative risk represents an assessment of the strength of the relevant association, independent of the clinical factors that are captured in the co-variates, in the multivariate model. In the New Jersey case, Landrigan, plaintiff had no asbestosis that would suggest he even had a serious exposure to asbestos. In a companion case, Caternicchio, the plaintiff claimed that he had asbestosis, and somehow this made the causal inference for his colorectal cancer stronger.[10] The epidemiologic studies he relied upon, however, stratified their analyses by length of exposure, and by radiographic category of asbestosis, neither of which suggested any relationship between radiographic findings and colorectal cancer outcome.
Perhaps because the authors are academics, they had to ask questions no one has every raised in a serious way in litigation, such as whether in addition to the clinical information, claimants could assert that toxicological data could be used to supplement a low (not greater than two) relative risk. The authors state the obvious; namely, toxicologic evidence is best suited to the assessment of general causation. They do not stop there, as they might have. Throwing their stated task of explicating the scientific foundations for specific causation inferences to the wind, the authors tell us that “[t]here is no formula for when such toxicologic evidence can tip the scales on the question of specific causation.”[11] And they wind up telling us vacuously that if the relevant epidemiology showed a small effect size, such as a two percent increased risk (RR = 1.02), then it would be unclear “how any animal data could cause one to substantially alter the best estimate of a human effect to reach a more-likely-than-not threshold.”[12] At this point in their paper, the authors seem to be discussing specific causation, but they offer nothing in the way of scientific evidence or examples of how toxicologic data could supplement a low relative risk (less than or equal to two) to permit a specific causation inference.
Idiopathy
When the analysis of the putative risk is done in a multivariate model that fairly covers the other relevant risks, relative risks less than 100 or so, suggest that there is a substantial baseline or background risk for the outcome of concern. When the relative risks identified in such analyses are less than 5 or so, the studies will suggest a reasonable proportion of so-called background cases with idiopathic (unknown) causes. Differential etiologies will have to rule out those mysterious idiopathogens.
If the putative specific cause is the only substance established to cause the outcome of concern, and the RR is greater than 1.0 and less than or equal to 2.0, by definition, there is a large base rate of the disease. No amount of hokey pokey will rule out the background causes. The authors deal with this scenario under the heading of differential etiology in the face of idiopathic causes, and characterize it as a “problem.”
Long story short, the authors conclude that “perhaps it is reasonable for courts to disregard idiopathic causes in those cases where idiopathic causes comprise a relatively small percent of all injuries.”[13] Such cases, however, by definition will diseases for which most causes are known, and the attributable fractions collectively for the known risks will be very high (say greater than 80 or 90%). Conversely, when the attributable fraction for all known risks is lower than 80%, the unexplained portion of the disease cases will represent idiopathic cases and causes that cannot be rule out with any confidence.
Differential etiology cannot work in the situation with a substantial baseline risk because there will be a disjunct (idiopathogen(s)) in the first statement of the syllogism, which cannot be ruled out. Thus, even if every other putative cause can be eliminated, the claimant will be left with the either the tortogen or the baseline risk as the cause of his injury, and the claimant will never arrive at a conclusion that is free of a disjunction that precludes judgment in his favor. In this scenario, the claimant must lose as a matter of law.
In their discussion of this issue, the authors note that this indeterminancy resulted in the exclusion of plaintiff’s expert witnesses in the notorious case of Milward v. Acuity Specialty Products Group, Inc.[14] In Milward, plaintiff had developed a rare variety of acute myeloid leukemia (AML), which had a large attributable fraction for idiopathic causation. This factual setting simply means that no known cause exists with a large relative risk, or even a small relative risk of 1.3 or so. Remarkably, these authors state that Milward “had prevailed on the general-causation issue” but in fact, no trial was ever held. The defense prevailed at the trial court by way of Rule 702 exclusion of plaintiff’s causation expert witnesses, but the First Circuit reversed and remanded for trial. The only prevailing that took place was the questionable avoidance of exclusion and summary judgment.[15]
On remand, the defense moved again to exclude plaintiffs’ expert witnesses on specific causation. Given that about 75% of AML cases are idiopathic, the court held that the plaintiffs’ expert witnesses attempt to proffer a differential etiology was fatally flawed.[16]
The authors cite the Milward specific causation decision, which in turn channeled the Restatement (Third) by couching the argument in terms of probability. If the claimant is left with a disjunction, [tortogen OR idiopathogen], then they suggest a probability value be assigned to the idiopathogen to support the inference that the probability that the tortogen was responsible for the claimant’s outcome [(1 – P(idiopathogen) x 100%]. Or in Judge Woodlock’s words:
“When a disease has a discrete set of causes, eliminating some number of them significantly raises the probability that the remaining option or options were the cause-in-fact of the disease. Restatement (Third) of Torts: Phys. & Emot. Harm § 28, cmt. c (2010) (‘The underlying premise [of differential etiology] is that each of the [ ] known causes is independently responsible for some proportion of the disease in a given population. Eliminating one or more of these as a possible cause for a specific plaintiff’s disease increases the probability that the agent in question was responsible for that plaintiff’s disease.’). The same cannot be said when eliminating a few possible causes leaves not only fewer possible causes but also a high probability that a cause cannot be identified. (‘When the causes of a disease are largely unknown . . . differential etiology is of little assistance.’).”[17]
The Milward approach is thus a vague, indirect invocation of relative risks and attributable fractions, without specifying the probabilities involved in quantitative terms. Like obscenity, judges are supposed to discern when the residual probability of idiopathy is too great to permit an inference of specific causation. Somehow, I have the sense we should be able to do better than this.
Multiple Risks
To their credit, the authors tackle the difficult cases that arise when multiple risks are present. Those multiple risks may be competing risks, including the tortogen, in which case not all participate in bringing about the outcome. Indeed, if there is a baseline risk, the result may still have come about from an idiopathogen. The discussion in Differential Etiologies take some twists and turns, and I will not discuss all of it here.
Strong tortogen versus one weak competing risk
The authors describe the scenario of strong tortogen versus a single competing risk as one of the “easy cases,” at least when the alternative cause appears to be de minimus:
“If the choice of whether one’s lung cancer was the result of a lifetime of heavy smoking or by a brief encounter with a substance for which there is a significant but weak correlation with lung cancer, in most situations it should be an easy task to rule out the other substance as the specific cause of the individual’s injury.”[18]
Unfortunately, the article’s discussion leaves everything rather vague, without quantifying the risks involved. We can, without too much effort, provide some numbers, although we cannot be sure that the authors would accept the resulting quantification. If the claimant’s lifetime of heavy smoking carried a relative risk of 30, and the claimant worked for a few years in a truck depot where he was exposed to diesel fumes that carried a relative risk of 1.2, it would seem that it should be “an easy task” to rule out diesel fumes and rule in smoking. Note however that ease of the inference is lubricated by the size of the relative risks involved, one much larger than two, and the other much smaller than two, and the absence of any suggestion of interaction or synergy between them. If the tortogen in this scenario is tobacco, the plaintiff wins readily. If the tortogen is diesel fumes, the plaintiff loses. Query, if this scenario arises in a case against the tobacco company, whether the alternative causation defense of exposure to diesel fumes fails as a matter of law?
Synergy between strong tortogen and strong competing risk
The authors cannot resist the temptation to cite the Mt. Sinai catechism[19] of multiplicative risk from smoking and asbestos exposure[20]:
“A well-known example of a synergistic effect is the combined effect of asbestos exposure and smoking on the likelihood of developing lung cancer. For long-term smokers, the relative risk of developing lung cancer compared to those who have never smoked is sometimes estimated to be in the range of 10.0. For individuals substantially exposed to asbestos, the relative risk of developing lung cancer compared to non-exposed individuals is in the range of 5.0. However, if one is unfortunate enough to have been exposed to asbestos and to have been a long-term smoker, the relative risk compared to those unexposed individuals who have not smoked exceeds the sum of the relative risks. One possibility is that the relationship is multiplicative, in the range of 50.0—i.e., a 49-fold risk increment.”[21]
The synergistic interaction is often raised in an attempt to defeat causal apportionment or avoid responsibility for the larger risk, as when smokers attempt to recover for lung cancer from asbestos exposure. Some courts have, however, permitted causal apportionment. In their analysis, the authors of Differential Etiologies simply wink and tell us that “[t]he calculation of synergistic effects is fairly complex.”[22]
Tortogen versus Multiple Risks
The scenario in which the tortogen has been “ruled in,” and is present in the claimant’s history, along with multiple other risks is more difficult than one might have imagined. The authors tell us that an individual claimant will fail to show that the tortogen is more likely than not a cause of her injury when one or more of the competing risks is stronger than the risk from the tortogen (assuming no synergy).[23] The authors’ analysis leaves unclear why the claimant does not similarly fail when the strength of the tortogen is equal to that of a competing risk. Similarly, the claimant would appear to have fallen short of the burden of proving the tortogen’s causal role when there are multiple competing risk factors that individually present smaller risks than the tortogen, but for which multiple subsets represent combined competing risks greater than the risk of the tortogen.
Concluding Thoughts
If the authors had framed the differential enterprise by the logic of iterative disjunctive syllogism, they would have recognized that the premise of the argument must contain the disjunction of all general causes that might have been a cause of the claimant’s disease or injury. Furthermore, unless the idiopathogen(s) is eliminated, which rarely is the case, we are left with a disjunction in the conclusion that prevents judgment for the plaintiff. The extensive analysis provided in Differential Etiologies ultimately must equate risk with cause, and it must do so on a probabilistic basis, even when the probabilities are left vague, and unquantified. Indeed, the authors come close to confronting the reality that we often do not know the cause of many individual’s diseases. We do know something about the person’s antecedent risks, and we can quantify and compare those risks. Noncommittally, the authors note that courts have been receptive to the practical solution of judging whether the tortogen’s relative risk was greater than two as a measure of sufficiency for specific causation, and that they “agree that theoretically this intuition has appeal.”[24]
Although I have criticized many aspect of the article, it is an important contribution to the legal study of specific causation. Its taxonomy will not likely be the final word on the subject, but it is a major step toward making sense of an area of the law long dominated by clinical black boxes and ipse dixits.
[1] Differential Etiologies at 885. The authors noted that their advice was “especially true in those case-control studies where the cases and controls are not drawn from the same defined population at risk for the outcome under investigation.”
[2] Differential Etiologies at 895.
[3] Differential Etiologies at 895 & n. 154, citing Betz v. Pneumo Abex, LLC, 44 A.3d 27, 51 (Pa. 2012).
[4] Differential Etiologies at 895 at n. 156.
[5] American Cancer Soc’y website, last visited June 19, 2022.
[6] I did not know at the time that Selikoff had failed the B-reader examination.
[7] See, e.g., Bowers v. Norfolk Southern Corp., 537 F. Supp. 2d 1343, 1359–60 (M.D. Ga. 2007) (“The differential diagnosis method has an inherent reliability; the differential etiology method does not. This conclusion does not suggest that the differential etiology approach has no merit. It simply means that courts, when dealing with matters of reliability, should consider opinions based on the differential etiology method with more caution. It also means that courts should not conflate the two definitions.”)
[8] Differential Etiologies at 899 & n.176, citing Landrigan v. Celotex Corp., 127 N.J. 404, 605 A.2d 1079, 1087 (1992).
[9] Differential Etiologies at 899 & n.179, citing Johnson & Johnson Talcum Powder Cases, 249 Cal. Rptr. 3d 642, 671–72 (Cal. Ct. App. 2019).
[10] Caterinicchio v. Pittsburgh Corning Corp., 127 N.J. 428, 605 A.2d 1092 (1992).
[11] Differential Etiologies at 899.
[12] Differential Etiologies at 900.
[13] Differential Etiologies at 915.
[14] 639 F.3d 11 (1st Cir. 2011).
[15] Does it require pointing out that the reversal took place with a highly questionable, unethical amicus brief submitted by a not-for-profit that was founded by the two plaintiffs’ expert witnesses excluded by the trial court? Given that the First Circuit reversed and remanded, and then later affirmed the exclusion of plaintiffs’ expert witnesses on specific causation, and the entry of judgment, the first appellate decision became unnecessary to the final judgment and no longer a clear precedent.
[16] Differential Etiologies at 912, discussing Milward v. Acuity Specialty Prods. Group, Inc., 969 F. Supp. 2d 101, 109 (D. Mass. 2013), aff’d sub. nom., Milward v. Rust-Oleum Corp., 820 F.3d 469, 471, 477 (1st Cir. 2016).
[17] Id., quoting from Milward.
[18] Differential Etiologies at 901.
[19] “The Mt. Sinai Catechism” (June 11, 2013).
[20] The mantra of 5-10-50 comes from early publications by Irving John Selikoff, and represents a misrepresentation of “never smoked regularly” as “never smoked,” and the use of a non-contemporaneous control group for the non-asbestos exposed, non-smoker base rate. When the external control group was updated to show a relative risk of 20, rather than 10 for smoking only, Selikoff failed to update his analysis. Selikoff’s protégés have recently updated the insulator cohort, repeating many of the original errors, but even so, finding only that “the joint effect of smoking and asbestos alone was additive.” See Steve Markowitz, Stephen Levin, Albert Miller, and Alfredo Morabia, “Asbestos, Asbestosis, Smoking and Lung Cancer: New Findings from the North American Insulator Cohort,” Am. J. Respir. & Critical Care Med. (2013).
[21] Differential Etiologies at 902. The authors do not cite the Selikoff publications, which repeated his dataset and his dubious interpretation endlessly, but rather cite David Faigman, et al., Modern Scientific Evidence: The Law and Science of Expert Testimony § 26.25. (West 2019–2020 ed.). To their credit, the authors describe multiplicative interaction as a possibility, but surely they known that plaintiffs’ expert witnesses recite the Mt. Sinai catechism in courtrooms all around the country, while intoning “reasonable degree of medical certainty.” The authors cite some contrary studies. Differential Etiologies at 902 n.188, citing several reviews including Darren Wraith & Kerrie Mengersen, “Assessing the Combined Effect of Asbestos Exposure & Smoking on Lung Cancer: A Bayesian Approach, 26 Stats. Med. 1150, 1150 (2007) (evidence supports more than an additive model and less than a multiplicative relation).”
[22] Differential Etiologies at 902 at n.189.
[23] Differential Etiologies at 905. The authors note that courts have admitted differential etiology testimony when the tortogen’s risk is greater than the risk from other known risks. Id. citing Cooper v. Takeda Pharms., 191 Cal. Rptr. 3d 67, 79 (Ct. App. 2015).
[24] Differential Etiologies at 896 & n.163.
