Admittedly, I am playing the role of the curmudgeon here by pointing out errors or confusions in the third edition of the Reference Manual. To be sure, there are many helpful and insightful discussions throughout the Manual, but they do not need to be revised. Presumably, the National Academies and the Federal Judicial Center are undertaking the project of producing a fourth edition because they understand that revisions, updates, and corrections are needed. Otherwise, why bother?
To be sure, there are aspects of the third edition’s epidemiology chapter that get some important points right.
(1) The chapter at least acknowledges that small relative risks (1 < RR <3) may be insufficient to support causal inferences.[1]
(2) The chapter correctly notes that the method known as “differential etiology” addresses only specific causation, and that the method presupposes that general causation has been established.[2]
(3) The third edition correctly observes that clinicians generally are not concerned with etiology as much as with diagnosis of disease.[3] The authors of the epidemiology chapter correctly observe that “[f]or many health conditions, the cause of the disease or illness has no relevance to its treatment, and physicians, therefore, do not employ this term or pursue that question.”[4] This observation alone should help trial courts question whether many clinicians have even the pretense of expertise to offer expert causation opinions.[5]
(4) With respect to so-called differential etiology, the third edition correctly states that this mode of reasoning is a logically valid argument if premises are true; that is, general causation must be established for each “differential etiology.” The epidemiology chapter observes that “like any scientific methodology, [differential etiology] can be performed in an unreliable manner.”[6]
(5) The third edition reports that the differential etiology argument as applied in litigation is often invalid because not all the differentials other than the litigation claim have been ruled out.[7]
(6) The third edition properly notes that for diseases for which the causes are largely unknown, such as most birth defects, a differential etiology is of little benefit.[8] Unfortunately, the third edition offered no meaningful guidance for how courts should consider differential etiologies offered when idiopathic cases make up something less “than largely,” (0% < Idiopathic < 10%, 20%, 30%, 40, 50%, etc.).The chapter acknowledges that:
“Although differential etiologies are a sound methodology in principle, this approach is only valid if … a substantial proportion of competing causes are known. Thus, for diseases for which the causes are largely unknown, such as most birth defects, a differential etiology is of little benefit.”[9]
Accordingly, many cases reject proffered expert witness testimony on differential etiology, when the witnesses failed to rule out idiopathic causes in the case at issue. What is a substantial proportion? Unfortunately, the third edition did not attempt to quantify or define “substantial.” The inability to rule out unknown etiologies remains the fatal flaw in much expert witness opinion testimony on specific causation.
Errant Opinions on Differential Etiology
The third edition’s treatment of differential etiology does leave room for improvement. One glaring error is the epidemiology chapter’s assertion that “differential etiology is a legal invention not used by physicians.”[10] Indeed, the third edition provides a definition for “differential etiology” that reinforces the error:
“differential etiology. Term used by the court or witnesses to establish or refute external causation for a plaintiff’s condition. For physicians, etiology refers to cause.”[11]
The third edition’s assertion about legal provenance and exclusivity can be quickly dispelled by a search on “differential etiology” in the National Library of Medicine’s PubMed database, which shows up dozens of results, going back to the early 1960s. Some citations are supplied in the notes.[12] A Google Ngram for “differential etiology” in American English shows prevalent usage well before any of the third edition’s cited cases:
The third edition’s erroneous assertion about the provenance of “differential etiology” has been echoed by other law professors. David Faigman, for instance, has claimed that in advancing differential etiologies, expert witnesses were inventing wholesale an approach that had no foundation or acceptance in their scientific disciplines:
“Differential etiology is ostensibly a scientific methodology, but one not developed by, or even recognized by, physicians or scientists. As described, it is entirely logical, but has no scientific methods or principles underlying it. It is a legal invention and, as such, has analytical heft, but it is entirely bereft of empirical grounding. Courts and commentators have so far merely described the logic of differential etiology; they have yet to define what that methodology is.”[13]
Faigman’s claim that courts and commentators have not defined the methodology underlying differential etiology is wrong. Just as hypothesis testing is predicated upon a probabilistic version of modus tollens, differential etiology is based upon “iterative disjunctive syllogism,” or modus tollendo ponens. Basic propositional logic recognizes that such syllogisms are valid arguments,[14] in which one of its premises is a disjunction (P v Q), and the other premise is the negation of one of the disjuncts:
P v Q
~P_____
∴ Q
If we expand the disjunctive premise to more than one disjunction, we can repeat the inference (iteratively), eliminating one disjunct at a time, until we arrive at a conclusion that is a simple, affirmative proposition, without any disjunctions in it.
P v Q v R
~P_____
∴ Q v R
~Q_____
∴ R
Hence, the term “iterative disjunctive syllogism.” Sherlock Holmes’ fans, of course, will recognize that iterative disjunctive syllogism is nothing other than the process of elimination, as explained by the hero of Sir Arthur Conan Doyle’s short stories.[15]
The fourth edition should correct the error of the third edition, and it should dispel the strange notion that differential etiology is not used by scientists or clinicians themselves.
Supreme Nonsense on Differential Etiology
In 2011, the Supreme Court addressed differential etiology in a case, Matrixx Initiatives, in stunningly irrelevant and errant dicta. The third edition did not discuss this troublesome case, in which the defense improvidently moved to dismiss a class action complaint for securities violations allegedly arising from the failure to disclose multiple adverse event reports of anosmia from the use of the defendant’s product, Zicam. The basic reason for the motion on the pleadings was that the plaintiffs’ failed to allege a statistically significant and causally related increased risk of anosmia. The Supreme Court made short work of the defense argument because material events, such as an FDA recall, did not require the existence of a causal relationship between Zicam use and anosmia. The defense complaints about statistical significance, causation, and their absence, were thus completely beside the point of the case. Nonetheless, it became the Court’s turn for improvidence in addressing statistical and causation issues not properly before it. With respect to causation, the Court offered this by way of obiter dictum:
“We note that courts frequently permit expert testimony on causation based on evidence other than statistical significance. See, e.g., Best v. Lowe’s Home Centers, Inc., 563 F. 3d 171, 178 (6th Cir 2009); Westberry v. Gislaved Gummi AB, 178 F. 3d 257, 263–264 (4th Cir. 1999) (citing cases); Wells v. Ortho Pharmaceutical Corp., 788 F. 2d 741, 744–745 (11th Cir. 1986). We need not consider whether the expert testimony was properly admitted in those cases, and we do not attempt to define here what constitutes reliable evidence of causation.”[16]
This part of the Court’s opinion was stunningly wrong about the Court of Appeals’ decisions on statistical significance[17] and on causation. The Best and the Westberry decisions were both cases that turned on specific, not general, causation. Statistical significance this was not part of the reasoning or rationale of the cited cases on specific caustion. Both cases assumed that general causation was established, and inquired into whether expert witnesses could reasonably and validly attribute the health outcome in the case to the exposures that were established causes of such outcomes. The Court’s selection of these cases, quite irrelevant to its discussion, appears to have come from the Solicitor General’s amicus brief in Matrixx, but mindlessly adopted by the Court.
Although cited for an irrelevant proposition, the Supreme Court’s selection of the Best’s case was puzzling because the Sixth Circuit’s discussion of the issue is particularly muddled. Here is the relevant language from Best:
“[A] doctor’s differential diagnosis is reliable and admissible where the doctor
(1) objectively ascertains, to the extent possible, the nature of the patient’s injury…,
(2) ‘rules in’ one or more causes of the injury using a valid methodology,
and
(3) engages in ‘standard diagnostic techniques by which doctors normally rule out alternative causes” to reach a conclusion as to which cause is most likely’.”[18]
Of course, as the authors of the third edition’s epidemiology chapter correctly note, physicians rarely use this iterative process to arrive at causes of diseases in an individual; they use it to identify the disease or disease process that is responsible for the patient’s signs and symptoms.[19] The Best court’s description does not make sense in that it characterizes the process as ruling in “one or more” causes, and then ruling out alternative causes. If an expert had ruled in only one cause, then there would be no need or opportunity to rule out an alternative cause. If the one ruled-in cause was ruled out for other reasons, then the expert witness would be left with a case of idiopathic disease.
In any event, differential etiology was irrelevant to the general causation issue raised by the defense in Matrixx Initiatives. After the Supreme Court correctly recognized that causation was largely irrelevant to the securities fraud claim, it had no reason to opine on general causation. Certainly, the Supreme Court had no reason to cite two cases on differential etiology in a case that did not even require allegations of general causation. The fourth edition of the Reference Manual should put Matrixx Initatives in its proper (and very limited) place.
[1] RMSE3d at 612 & n.193 (noting that “one commentator contends that, because epidemiology is sufficiently imprecise to accurately measure small increases in risk, in general, studies that find a relative risk less than 2.0 should not be sufficient for causation. The concern is not with specific causation but with general causation and the likelihood that an association less than 2.0 is noise rather than reflecting a true causal relationship. See Michael D. Green, “The Future of Proportional Liability,” in Exploring Tort Law (Stuart Madden ed., 2005); see also Samuel M. Lesko & Allen A. Mitchell, “The Use of Randomized Controlled Trials for Pharmacoepidemiology Studies,” in Pharmacoepidemiology 599, 601 (Brian Strom ed., 4th ed. 2005) (“it is advisable to use extreme caution in making causal inferences from small relative risks derived from observational studies”); Gary Taubes, “Epidemiology Faces Its Limits,” 269 Science 164 (1995) (explaining views of several epidemiologists about a threshold relative risk of 3.0 to seriously consider a causal relationship); N.E. Breslow & N.E. Day, “Statistical Methods in Cancer Research,” in The Analysis of Case-Control Studies 36 (IARC Pub. No. 32, 1980) (“[r]elative risks of less than 2.0 may readily reflect some unperceived bias or confounding factor”); David A. Freedman & Philip B. Stark, “The Swine Flu Vaccine and Guillain-Barré Syndrome: A Case Study in Relative Risk and Specific Causation,” 64 Law & Contemp. Probs. 49, 61 (2001) (“If the relative risk is near 2.0, problems of bias and confounding in the underlying epidemiologic studies may be serious, perhaps intractable.”). For many other supporting comments and observations, see “Small Relative Risks and Causation” (June 28, 2022).
[2] RMSE3d. at 618 (“Although differential etiologies are a sound methodology in principle, this approach is only valid if general causation exists … .”). In the case of a novel putative cause, the case may give rise to a hypothesis that the putative cause can cause the outcome, in general, and did so in the specific case. That hypothesis must, of course, then be tested and supported by appropriate analytical methods before it can be accepted for general causation and as a putative specific cause in a particular individual.
[3] RMSE3d at 617.
[4] RMSE3d at 617 & n. 211 (citing Zandi v. Wyeth, Inc., No. 27-CV-06-6744, 2007 WL 3224242 (D. Minn. Oct. 15, 2007) (observing that physicians do assess the cause of patients’ breast cancers)).
[5] See, e.g., Tamraz v. BOC Group Inc., No. 1:04-CV-18948, 2008 WL 2796726 (N.D.Ohio July 18, 2008)(denying Rule 702 challenge to treating physician’s causation opinion), rev’d sub nom. Tamraz v. Lincoln Elec. Co., 620 F.3d 665 (6th Cir. 2010)(carefully reviewing record of trial testimony of plaintiffs’ treating physician; reversing judgment for plaintiff based in substantial part upon treating physician’s speculative causal assessment created by plaintiffs’ counsel), cert. denied, ___ U.S. ___ , 131 S. Ct. 2454 (2011).
[6] RMSE3d at 617-18 & n. 215.
[7] See, e.g, Milward v. Acuity Specialty Products Group, Inc., Civil Action No. 07–11944–DPW, 2013 WL 4812425 (D. Mass. Sept. 6, 2013) (excluding plaintiffs’ expert witnesses on specific causation), aff’d sub nom., Milward v. Rust-Oleum Corp., 820 F.3d 469 (1st Cir. 2016). Interestingly, the earlier appellate journey taken by the Milward litigants resulted in a reversal of a Rule 702 exclusion of plaintiff’s general causation expert witnesses. That reversal meant that there was no longer a final judgment. The exclusion of specific causation witnesses was affirmed by the First Circuit, and the general causation opinion was no longer necessary to the final judgment. See “Differential Diagnosis in Milward v. Acuity Specialty Products Group” (Sept. 26, 2013); “Differential Etiology and Other Courtroom Magic” (June 23, 2014).
[8] RMSE3d at 617-18 & n. 214.
[9] See RMSE at 618 (internal citations omitted).
[10] RMSE3d at 691 (emphasis added).
[11] RMSE3d at 743.
[12] See, e.g., Kløve & D. Doehring, “MMPI in epileptic groups with differential etiology,” 18 J. Clin. Psychol. 149 (1962); Kløve & C. Matthews, “Psychometric and adaptive abilities in epilepsy with differential etiology,” 7 Epilepsia 330 (1966); Teuber & K. Usadel, “Immunosuppression in juvenile diabetes mellitus? Critical viewpoint on the treatment with cyclosporin A with consideration of the differential etiology,” 103 Fortschr. Med. 707 (1985); G.May & W. May, “Detection of serum IgA antibodies to varicella zoster virus (VZV)–differential etiology of peripheral facial paralysis. A case report,” 74 Laryngorhinootologie 553 (1995); Alan Roberts, “Psychiatric Comorbidity in White and African-American Illicity Substance Abusers” Evidence for Differential Etiology,” 20 Clinical Psych. Rev. 667 (2000); Mark E. Mullinsa, Michael H. Leva, Dawid Schellingerhout, Gilberto Gonzalez, and Pamela W. Schaefera, “Intracranial Hemorrhage Complicating Acute Stroke: How Common Is Hemorrhagic Stroke on Initial Head CT Scan and How Often Is Initial Clinical Diagnosis of Acute Stroke Eventually Confirmed?” 26 Am. J. Neuroradiology 2207 (2005); Qiang Fua, et al., “Differential Etiology of Posttraumatic Stress Disorder with Conduct Disorder and Major Depression in Male Veterans,” 62 Biological Psychiatry 1088 (2007); Jesse L. Hawke, et al., “Etiology of reading difficulties as a function of gender and severity,” 20 Reading and Writing 13 (2007); Mastrangelo, “A rare occupation causing mesothelioma: mechanisms and differential etiology,” 105 Med. Lav. 337 (2014).
[13] David L. Faigman & Claire Lesikar, “Organized Common Sense: Some Lessons from Judge Jack Weinstein’s Uncommonly Sensible Approach to Expert Evidence,” 64 DePaul L. Rev. 421, 439, 444 (2015). See also “David Faigman’s Critique of G2i Inferences at Weinstein Symposium” (Sept. 25, 2015).
[14] See Irving Copi & Carl Cohen Introduction to Logic at 362 (2005).
[15] See, e.g., Doyle, The Blanched Soldier (“…when you have eliminated all which is impossible, then whatever remains, however improbable, must be the truth.”); Doyle, The Beryl Coronet (“It is an old maxim of mine that when you have excluded the impossible, whatever remains, however improbable, must be the truth.”); Doyle, The Hound of the Baskervilles (1902) (“We balance probabilities and choose the most likely. It is the scientific use of the imagination.”); Doyle, The Sign of the Four, ch 6 (1890)(“‘You will not apply my precept’, he said, shaking his head. ‘How often have I said to you that when you have eliminated the impossible, whatever remains, however improbable, must be the truth? We know that he did not come through the door, the window, or the chimney. We also know that he could not have been concealed in the room, as there is no concealment possible. When, then, did he come?”)
[16] Matrixx Initiatives, Inc. v. Siracusano, 131 S. Ct. 1309, 1319 (2011).
[17] The citation to Wells was clearly wrong in that the plaintiffs in that case had, in fact, relied upon studies that were nominally statistically significant, and so the Wells court could not have held that statistical significance was unnecessary.
[18] Best v. Lowe’s Home Centers, Inc., 563 F.3d 171, 179, 183-84 (6th Cir. 2009).
[19] See generally Harold C. Sox, Michael C. Higgins, and Douglas K. Owens, Medical Decision Making (2d ed. 2014).
