For your delectation and delight, desultory dicta on the law of delicts.

Omalu and Science — A Bad Weld

October 22nd, 2016

Bennet Omalu is a star of the silver screen and in the minds of conspiratorial thinkers everywhere. Actually Will Smith[1] stood in for Omalu in the movie Concussion (2015), but Smith’s skills as an actor bring out the imaginary best in Omalu’s persona.

Chronic Traumatic Encephalopathy (CTE) is the name that Bennet Omalu, a pathologist, gave to the traumatic brain injuries resulting from repeated concussions experienced by football players.[2]  The concept is not particularly new; the condition of dementia pugilistica had been described previously in boxers. What was new with Omalu was his fervid imagination and his conspiratorial view of the world.[3] The movie Concussion  actually gives an intimation of some of the problems in Omalu’s scientific work.  See, e.g., Daniel Engber, “Concussion Lies: The film about the NFL’s apparent CTE epidemic feeds the pervasive national myths about head trauma,” Slate (Dec. 21 2015); Bob Hohler, “BU rescinds award to ‘Concussion’ trailblazer,” Boston Globe (June 16, 2016).

Omalu has more dubious claims to fame. He has not cabined his unique, stylized approach to science to the subject of head trauma. Although Omalu is a pathologist, not a clinician, Omalu recently he weighed in with observations that Hillary Clinton was definitely unwell. Indeed, Bennet Omalu has now made a public nuisance of himself by floating conspiratorial theories that Hilary Clinton has been poisoned. Cindy Boren, “The man who discovered CTE thinks Hillary Clinton may have been poisoned,” Wash. Post (Sept. 12, 2016); Christine Rushton, “‘Concussion’ doctor suggests without evidence that poison a factor in Clinton’s illness,” Los Angeles Times. (Sept. 13, 2016).

In the courtroom, in civil cases, Omalu has a poor track record for scientific rigor. The United States Court of Appeals, for the Third Circuit, which can be tough and skeptical of Rule 702 expert witness exclusions, readily affirmed an exclusion of Omalu’s testimony in Pritchard v. Dow Agro Sciences, 705 F. Supp. 2d 471 (W.D. Pa. 2010), aff’d, 430 F. App’x 102, 104 (3d Cir. 2011). In Pritchard, Omalu was caught misrepresenting the statistical data from published studies in a so-called toxic tort case. Fortunately, robust gatekeeping was able to detoxify the proffered testimony.[4]

More recently, Omalu was at it again in a case in which a welder claimed that exposure to welding and solvent fumes caused him to develop Parkinson’s disease. Brian v. Association of Independent Oil Distributors, No. 2011-3413, Westmoreland Cty. Ct. Common Pleas, Order of July 18, 2016. [cited here as Order].

James G. Brian developed Parkinson disease (PD), after 30 years of claimed exposure to welding and solvent fumes. It is America, so Brian sued Lincoln Electric and various chemical companies on his theory that his PD was caused by his welding and solvent exposures, either alone or together. Now although manganese in very high exposures can cause a distinctive movement disorder, manganism, manganese in welding fume does not cause PD in humans.[5] Omalu was undeterred, however, and proceeded by conjecturing that welding fume interacted with solvent fumes to cause Brian’s PD.

At the outset of the case, Brian intended to present testimony of expert witnesses, Bennet Omalu, Richard A. Parent, a toxicologist, and Jordan Loyal Holtzman, a pharmacologist.  Parent commenced giving a deposition, but became so uncomfortable with his own opinion that he put up a white flag at the deposition, and withdrew from the case.  On sober reflection, Holtzman also withdrew from the case.

Omalu was left alone, to make the case on general and specific causation. Defendant Lincoln Electric and others moved to exclude Omalu, under Pennsylvania’s standard for admissibility of expert witness opinion testimony, which is based upon a patch-work version of Frye v. United States, 293 F. 1013 (D. C. Cir. 1923).

Invoking a quirky differential diagnosis, and an idiosyncratic reading of Sir Austin Bradford Hill’s work, Omalu defended his general and specific causation opinions. After briefing and a viva voce hearing, President Judge Richard E. McCormick ruled that Omalu had misapplied both methodologies in reaching his singular opinion. Order at 8.

Omalu did not make the matter easy for Judge McCormick. There was no question that Brian had PD.  Every clinician who had examined him made the diagnosis. Knowing that PD is generally regarded as idiopathic, with no known cause, Omalu thought up a new diagnosis: chronic toxic encephalopathy.

When confronted with the other clincians’ diagnoses, Omalu did not dispute the diagnosis of PD. Instead, he attempted to evade the logical implications of the diagnosis of idiopathic PD by continually trying to change the terminology to suit his goals. Judge McCormick saw through Omalu’s semantic evasions, which bolstered the case for excluding him at trial.

Madness to His Method

In scrutinizing Omalu’s opinions, Judge McCormick found more madness than method. Omalu claimed that he randomly selected studies to rely upon, and he failed to explain the strengths and weaknesses of the cited studies when he formed his opinion.

Despite his claim to have randomly selected studies, Omalu remarkably managed to ignore epidemiologic studies that were contrary to his causal conclusions. Order at 9.  Indeed, Omalu missed more than half the published studies on welding and PD.  Not surprisingly, Omalu did not record his literature search; nor could explain, in deposition or at the court hearing, his inclusionary or exclusionary criteria for pertinent studies. Id. at 10. When confronted about his “interaction” opinions concerning welding and solvent fumes, Omalu cited several studies, none of which measured or assessed combined exposures.  Some of the papers flatly contradicted Omalu’s naked assertions. Id. at 9.

Judge McCormick rejected Omalu’s distorted invocation of the Bradford Hill factors to support a causal association when no association had yet been found. The court quoted from the explanation provided by Prof. James A. Mortimer, the defense neuroepidemiologist, at the Frye hearing:

“First, the Bradford Hill criteria should not be applied until you have ruled out a chance association, which [Omalu] did not do. In fact, as I will point out, carefully done epidemiologic studies will show there is no increased risk of Parkinson’s disease with exposure to welding fume and/or solvents, therefore the application of these criteria is inappropriate.”

Order at 11, citing to and quoting from Frye Hearing at 318 (Oct. 14, 2015).

When cornered, Omalu asserted that he never claimed that Mr. Brian’s PD was caused by welding or solvents; rather his contention was simply that occupational exposures had created a “substantial increased risk” of PD. Id. at 14. Risk creation, however, is not causation; and Omalu had not even shown unquantified evidence of increased risk before Brian developed PD. The court found that Omalu had not used any appropriate methodology with respect to general causation. Id. at 14.

Specific Causation

Undaunted, Omalu further compromised his credibility by claiming that Bradford Hill’s factors allowed him to establish specific causation, even in the absence of general causation. Id. at 12. Omalu suggested that he had performed a differential diagnosis, even though he is not a clinician, and as a pathologist had not evaluated any brain tissue. Id. at 10. The court deftly saw through these ruses. Id. at 11.

Judge McCormick’s conclusion should be a precautionary lesson to future courts that must gatekeep Omalu’s opinions, or Omalu-like opinions:

“In conclusion, we agree with the Defendants that while Dr. Omalu’s stated methodology in this case is generally accepted in the medical and scientific community, Dr. Omalu failed to properly apply it. He misused and demonstrated a lack of understanding of the Bradford Hill criteria and the Schaumburg criteria when he attempted to employ these methodologies to conduct a differential diagnosis or differential etiology analysis.”

Id. at 16. Gatekeeping is sometimes viewed as more difficult in Frye jurisdictions, but the exclusion of Omalu shows that it can be achieved when expert witnesses deviate materially from scientifically standard methodology.

[1] For other performances by Will Smith in this vein, see Six Degrees of Separation (1993); Focus (2015).

[2] See Bennet I. Omalu, Steven DeKosky, Ryan Minster, M. Ilyas Kamboh, Ronald Hamilton, Cyril H. Wecht, “Chronic Traumatic Encephalopathy in a National Football League Player, Part I,” 57 Neurosurgery 128 (2005); Bennet I. Omalu, Steven DeKosky, Ronald Hamilton, Ryan Minster, M. Ilyas Kamboh, Abdulrezak Shakir, and Cyril H. Wecht, “Chronic Traumatic Encephalopathy in a National Football League Player, Part II,” 59 Neurosurgery 1086 (2006).

[3] See Jeanne Marie Laskas, “The Doctor the NFL Tried to Silence,” Wall St. J. (Nov. 24, 2015).

[4] SeePritchard v. Dow Agro – Gatekeeping Exemplified” (Aug. 25, 2014).

[5] See, e.g., Marianne van der Mark, Roel Vermeulen, Peter C.G. Nijssen, Wim M. Mulleners, Antonetta M.G. Sas, Teus van Laar, Anke Huss, and Hans Kromhout, “Occupational exposure to solvents, metals and welding fumes and risk of Parkinson’s disease,” 21 Parkinsonism Relat Disord. 635 (2015); James Mortimer, Amy Borenstein & Laurene Nelson, Associations of Welding and Manganese Exposure with Parkinson’s Disease: Review and Meta-Analysis, 79 Neurology 1174 (2012); Joseph Jankovic, “Searching for a relationship between manganese and welding and Parkinson’s disease,” 64 Neurology 2012 (2005).

 Another Haack Article on Daubert

October 14th, 2016

In yet another law review article on Daubert, Susan Haack has managed mostly to repeat her past mistakes, while adding a few new ones to her exegesis of the law of expert witnesses. See Susan Haack, “Mind the Analytical Gap! Tracing a Fault Line in Daubert,” 654 Wayne L. Rev. 653 (2016) [cited as Gap].  Like some other commentators on the law of evidence, Haack purports to discuss this area of law without ever citing or quoting the current version of the relevant statute, Federal Rule of Evidence 703. She pours over Daubert and Joiner, as she has done before, with mostly the same errors of interpretation. In discussing Joiner, Haack misses the importance of the Supreme Court’s reversal of the 11th Circuit’s asymmetric standard of Rule 702 trial court decisions. Gap at 677. And Haack’s analysis of this area of law omits any mention of Rule 703, and its role in Rule 702 determinations. Although you can safely skip yet another Haack article, you should expect to see this one, along with her others, cited in briefs, right up there with David Michael’s Manufacturing Doubt.

A Matter of Degree

“It may be said that the difference is only one of degree. Most differences are, when nicely analyzed.”[1]

Quoting Holmes, Haack appears to complain that the courts’ admissibility decisions on expert witnesses’s opinions are dichotomous and categorical, whereas the component parts of the decisions, involving relevance and reliability, are qualitative and gradational. True, true, and immaterial.

How do you boil a live frog so it does not jump out of the water?  You slowly turn up the heat on the frog by degrees.  The frog is lulled into complacency, but at the end of the process, the frog is quite, categorically, and sincerely dead. By a matter of degrees, you can boil a frog alive in water, with a categorically ascertainable outcome.

Humans use categorical assignments in all walks of life.  We rely upon our conceptual abilities to differentiate sinners and saints, criminals and paragons, scholars and skells. And we do this even though IQ, and virtues, come in degrees. In legal contexts, the finder of fact (whether judge or jury) must resolve disputed facts and render a verdict, which will usually be dichotomous, not gradational.

Haack finds “the elision of admissibility into sufficiency disturbing,” Gap at 654, but that is life, reason, and the law. She suggests that the difference in the nature of relevancy and reliability on the one hand, and admissibility on the other, creates a conceptual “mismatch.” Gap at 669. The suggestion is rubbish, a Briticism that Haack is fond of using herself.  Clinical pathologists may diagnose cancer by counting the number of mitotic spindles in cells removed from an organ on biopsy.  The number may be characterized by as a percentage of cells in mitosis, a gradational that can run from zero to 100 percent, but the conclusion that comes out of the pathologist’s review is a categorical diagnosis.  The pathologist must decide whether the biopsy result is benign or malignant. And so it is with many human activities and ways of understanding the world.

The Problems with Daubert (in Haack’s View)

Atomism versus Holism

Haack repeats a litany of complaints about Daubert, but she generally misses the boat.  Daubert was decisional law, in 1993, which interpreted a statute, Federal Rule of Evidence 702.  The current version of Rule 702, which was not available to, or binding on, the Court in Daubert, focuses on both validity and sufficiency concerns:

A witness who is qualified as an expert by knowledge, skill, experience, training, or education may testify in the form of an opinion or otherwise if:

(a) the expert’s scientific, technical, or other specialized knowledge will help the trier of fact to understand the evidence or to determine a fact in issue;

(b) the testimony is based on sufficient facts or data;

(c) the testimony is the product of reliable principles and methods; and

(d) the expert has reliably applied the principles and methods to the facts of the case.

Subsection (b) renders most of Haack’s article a legal ignoratio elenchi.

Relative Risks Greater Than Two

Modern chronic disease epidemiology has fostered an awareness that there is a legitimate category of disease causation that involves identifying causes that are neither necessary nor sufficient to produce their effects. Today it is a commonplace that an established cause of lung cancer is cigarette smoking, and yet, not all smokers develop lung cancer, and not all lung cancer patients were smokers.  Epidemiology can identify lung cancer causes such as smoking because it looks at stochastic processes that are modified from base rates, or population rates. This model of causation is not expected to produce uniform and consistent categorical outcomes in all exposed individuals, such as lung cancer in all smokers.

A necessary implication of categorizing an exposure or lifestyle variable as a “cause,” in this way is that the evidence that helps establish causation cannot answer whether a given individual case of the outcome of interest was caused by the exposure of interest, even when that exposure is a known cause.  We can certainly say that the exposure in the person was a risk for developing the disease later, but we often have no way to make the individual attribution.  In some cases, more the exception than the rule, there may be an identified mechanism that allows the detection of a “fingerprint” of causation. For the most part, however, risk and cause are two completely different things.

The magnitude of risk, expressed as a risk ratio, can be used to calculate a population attributable risk, which can in turn, with some caveats, be interpreted as approximating a probability of causation.  When the attributable risk is 95%, as it would be for people with light smoking habits and lung cancer, treating the existence of the prior risk as evidence of specific causation seems perfectly reasonable.  Treating a 25% attributable risk as evidence to support a conclusion of specific causation, without more, is simply wrong.  A simple probabilistic urn model would tell us that we would most likely be incorrect if we attributed a random case to the risk based upon such a low attributable risk.  Although we can fuss over whether the urn model is correct, the typical case in litigation allows no other model to be asserted, and it would be the plaintiffs’ burden of proof to establish the alternative model in any event.

As she has done many times before, Haack criticizes Judge Kozinski’s opinion in Daubert,[2] on remand, where he entered judgment for the defendant because further proceedings were futile given the small relative risks claimed by plaintiffs’ expert witnesses.  Those relative risks, advanced by Shanna Swan and Alan Done, lacked reliability; they were the product of a for-litigation juking of the stats that were the original target of the defendant and the medical community in the Supreme Court briefing.  Judge Kozinski simplified the case, using a common legal strategem of assuming arguendo that general causation was established.  With this assumption favorable to plaintiffs made, but never proven or accepted, Judge Kozinski could then shine his analytical light on the fatal weakness of the specific causation opinions.  When all the hand waving was put to rest, all that propped up the plaintiff’s specific causation claim was the existence of a claimed relative risk, which was less than two. Haack is unhappy with the analytical clarity achieved by Kozinski, and implicitly urges a conflation of general and specific causation so that “all the evidence” can be counted.  The evidence of general causation, however, does not advance plaintiff’s specific causation case when the nature of causation is the (assumed) existence of a non-necessary and non-sufficient risk. Haack quotes Dean McCormick as having observed that “[a] brick is not a wall,” and accuses Judge Kozinski of an atomistic fallacy of ruling out a wall simply because the party had only bricks.  Gap at 673, quoting from Charles McCormick, Handbook of the Law of Evidence at 317 (1954).

There is a fallacy opposite to the atomistic fallacy, however, namely the holistic “too much of nothing fallacy” so nicely put by Poincaré:

“Science is built up with facts, as a house is with stones. But a collection of facts is no more a science than a heap of stones is a house.”[3]

Poincaré’s metaphor is more powerful than Haack’s call for holistic evidence because it acknowledges that interlocking pieces of evidence may cohere as a building, or they may be no more than a pile of rubble.  Poorly constructed walls may soon revert to the pile of stones from which they came.

Haack proceeds to criticize Judge Kozinski for his “extraordinary argument” that

“(a) equates degrees of proof with statistical probabilities;

(b) assesses each expert’s testimony individually; and

(c) raises the standard of admissibility under the relevance prong to the standard of proof.”

Gap at 672.

Haack misses the point that a low relative risk, with no other valid evidence of specific causation, translates into a low probability of specific causation, even if general causation were apodictically certain. Aggregating the testimony, say between  animal toxicologists and epidemiologists, simply does not advance the epistemic ball on specific causation because all the evidence collectively does not help identify the cause of Jason Daubert’s birth defects on the very model of causation that plaintiffs’ expert witnesses advanced.

All this would be bad enough, but Haack then goes on to commit a serious category mistake in confusing the probabilistic inference (for specific causation) of an urn model with the prosecutor’s fallacy of interpreting a random match probability as the evidence of innocence. (Or the complement of the random match probability as the evidence of guilt.) Judge Kozinski was not working with random match probabilities, and he did not commit the prosecutor’s fallacy.

Take Some Sertraline and Call Me in the Morning

As depressing as Haack’s article is, she manages to make matters even gloomier by attempting a discussion of Judge Rufe’s recent decision in the sertraline birth defects litigation. Haack’s discussion of this decision illustrates and typifies her analyses of other cases, including various decisions on causation opinion testimony on phenylpropanolamine, silicone, bendectin, t-PA, and other occupational, environmental, and therapeutic exposures. Maybe 100 mg sertraline is in order.

Haack criticizes what she perceives to be the conflation of admissibility and sufficiency issues in how the sertraline MDL court addressed the defendants’ motion to exclude the proffered testimony of Dr. Anick Bérard. Gap at 683. The conflation is imaginary, however, and the direct result of Haack’s refusal to look at the specific, multiple methodological flaws in plaintiffs’ expert witness Anick Bérard’s methodologic approach taken to reach a causal conclusion. These flaws are not gradational, and they are detailed in the MDL court’s opinion[4] excluding Anick Bérard. Haack, however, fails to look at the details. Instead Haack focuses on what she suggests is the sertraline MDL court’s conclusion that epidemiology was necessary:

“Judge Rufe argues that reliable testimony about human causation should generally be supported by epidemiological studies, and that ‘when epidemiological studies are equivocal or inconsistent with a causation opinion, experts asserting causation opinions must thoroughly analyze the strengths and weaknesses of the epidemiological research and explain why [it] does not contradict or undermine their opinion’. * * *

Judge Rufe acknowledges the difference between admissibility and sufficiency but, when it comes to the part of their testimony he [sic] deems inadmissible, his [sic] argument seems to be that, in light of the defendant’s epidemiological evidence, the plaintiffs’ expert testimony is insufficient.”

Gap at 682.

This précis is a remarkable distortion of the material facts of the case. There was no plaintiffs’ epidemiology evidence and defendants’ epidemiologic evidence.  Rather there was epidemiologic evidence, and Bérard ignored, misreported, or misrepresented a good deal of the total evidentiary display. Bérard embraced studies when she could use their risk ratios to support her opinions, but criticized or ignored the same studies when their risk ratios pointed in the direction of no association or even of a protective association. To add to this methodological duplicity, Anick Bérard published many statements, in peer-reviewed journals, that sertraline was not shown to cause birth defects, but then changed her opinion solely for litigation. The court’s observation that there was a need for consistent epidemiologic evidence flowed not only from the conception of causation (non-necessary, not sufficient), but from Berard’s and her fellow plaintiffs’ expert witnesses’ concessions that epidemiology was needed.  Haack’s glib approach to criticizing judicial opinions fails to do justice to the difficulties of the task; nor does she advance any meaningful criteria to separate successful from unsuccessful efforts.

In attempting to make her case for the gradational nature of relevance and reliability, Haack acknowledges that the details of the evidence relied upon can render the evidence, and presumably the conclusion based thereon, more or less reliable.  Thus, we are told that epidemiologic studies based upon self-reported diagnoses are highly unreliable because such diagnoses are often wrong. Gap at 667-68. Similarly, we are told that in consider a claim that a plaintiff suffered an adverse effect from a medication, that epidemiologic evidence showing a risk ratio of three would not be reliable if it had inadequate or inappropriate controls,[5] was not double blinded, and lacked randomization. Gap at 668-69. Even if the boundaries between reliable and unreliable are not always as clear as we might like, Haack fails to show that the gatekeeping process lacks a suitable epistemic, scientific foundation.

Curiously, Haack calls out Carl Cranor, plaintiffs’ expert witness in the Milward case, for advancing a confusing, vacuous “weight of the evidence” rationale for the methodology employed by the other plaintiffs’ causation expert witnesses in Milward.[6] Haack argues that Cranor’s invocation of “inference to the best explanation” and “weight of the evidence” fails to answer the important questions at issue in the case, namely how to weight the inference to causation as strong, weak, or absent. Gap at 688 & n. 223, 224. And yet, when Haack discusses court decisions that detailed voluminous records of evidence about how causal inferences should be made and supported, she flies over the details to give us confused, empty conclusions that the trial courts conflated admissibility with sufficiency.

[1] Rideout v. Knox, 19 N.E. 390, 392 (Mass. 1892).

[2] Daubert v. Merrell Dow Pharm., Inc., 43 F.3d 1311, 1320 (9th Cir. 1995).

[3] Jules Henri Poincaré, La Science et l’Hypothèse (1905) (chapter 9, Les Hypothèses en Physique)( “[O]n fait la science avec des faits comme une maison avec des pierres; mais une accumulation de faits n’est pas plus une science qu’un tas de pierres n’est une maison.”).

[4] In re Zoloft Prods. Liab. Litig., 26 F. Supp. 3d 466 (E.D. Pa. 2014).

[5] Actually Haack’s suggestion is that a study with a relative risk of three would not be very reliable if it had no controls, but that suggestion is incoherent.  A risk ratio could not have been calculated at all if there had been no controls.

[6] Milward v. Acuity Specialty Prods., 639 F.3d 11, 17-18 (1st Cir. 2011), cert. denied, 132 S.Ct. 1002 (2012).

Toward Better Definitions & Assessments of Conflicts of Interest in Science

October 13th, 2016

In capitalist and in communist societies, industry has a responsibility to conduct research on health and safety concerns. For corporate research to be credible, it should be methodologically sound, transparent, and available. So should non-corporate research.

In the United States and in Europe, much important research is done only by private corporate sponsors. Of course, private funding of research raises questions about potential conflicts of interest (COIs), but political frenzy over such COIs is a serious diversion often motivated by a desire to live in a faith-based world in which industry and chemicals are demonized far beyond what even precautionary principles would support. Susan Sarandon’s superstitions about the herbicide Round Up come to mind.

Although members of the Lobby, the Litigation Industry, and the environmental groups of the less rational kind frequently find their knickers in a knot over corporate scientific COIs, the fact is that publicly funded and self-styled “public interest” research is often afflicted by non-financial COIs that are more mind numbing than the anticipation of money.[1] Some groups, such as the Society of Toxicology, have implemented more complete definitions of COI to include advocacy and positional conflicts.[2]

Joseph Huggard recently posted an interesting piece at Innovative Science Solutions’ blog, on the need to “Follow the Science Not the Money,” to remind us of the first principle, that research should be evaluated primarily on its merits, and not on its perceived or imagined COIs. Huggard likens the current situation of proliferating ad hominem attacks to less talented footballer who approaches the game thinking “If you can’t play the ball, play the man.” (Or if you are Donald Trump, then play the ref.)

Huggard cites an interesting meta-observational study in which researchers attempted to obtain research protocols from epidemiologic studies on phthalate exposure. Not surprisingly, researchers who published studies that purported to find adverse associations involving phthalates were three times less likely to share their study protocols.[3] A request for study protocols is hardly an intrusive or difficult request to meet. Of course, there are “reasons,” such as researchers’ desire to privilege their methods when so-called positive studies will serve as stepping stones to funding for future studies, but future studies should be conditioned on making past protocols available, and the failure to share protocols generally is pretty dubious scientific behavior.

As grim as the situation has been in the United States, Huggard suggests that an upcoming Luxembourg Chamber of Commerce conference this week, on October 10th, will seek to redress the imbalance in European COI rhetoric by calling attention to the importance of non-financial conflicts and biases.[4] Let’s hope so, but the more likely outcome is that the Chamber of Commerce’s sponsorship will disqualify any conference recommendations among the “political scientists,” those who practice science to achieve political aims.

[1] Simon N. Young, “Bias in the research literature and conflict of interest: an issue for publishers, editors, reviewers and authors, and it is not just about the money,” 34 J. Psychiatry & Neurosci. 412 (2009) (positional conflicts, based upon prior beliefs, can create much more intractable bias than financial rewards). See also “Conflict Over Conflicts of Interest” (July 12, 2015); “Conflicts of Interest in Asbestos Studies – the Plaintiffs’ Double Standard” (Sept. 24, 2013); “Conflicted Public Interest Groups” (Nov 3, 2013).

[2] See, e.g., Society of Toxicology, Conflict of Interest, Bias and Advocacy: Definitions and Statements.

[3] Gerard M.H. Swaen, Miriam J.E. Urlings, and Maurice P. Zeegers, “Outcome reporting bias in observational epidemiology studies on phthalates,” 26 Ann. Epidemiol. 597E4 (2016)

[4] “Managing Bias and Conflict of Interest: Ensuring that Policy-Makers and Regulators Access the Best Quality Scientific Advice,” at the Chambre de Commerce Luxembourg, at 7, rue Alcide de Gasperi, Luxembourg (Kirchberg).

New Jersey Kemps Ovarian Cancer – Talc Cases

September 16th, 2016

Gatekeeping in many courtrooms has been reduced to requiring expert witnesses to swear an oath and testify that they have followed a scientific method. The federal rules of evidence and most state evidence codes require more. The law, in most jurisdictions, requires that judges actively engage with, and inspect, the bases for expert witnesses’ opinions and claims to determine whether expert witnesses who want to heard in a courtroom have actually, faithfully followed a scientific methodology.  In other words, the law requires judges to assess the scientific reasonableness of reliance upon the actual data cited, and to evaluate whether the inferences drawn from the data, to reach a stated conclusion, are valid.

We are getting close to a quarter of a century since the United States Supreme Court outlined the requirements of gatekeeping, in Daubert v. Merrell Dow Pharms., Inc., 509 U.S. 579 (1993). Since the Daubert decision, the Supreme Court’s decisional law, and changes in the evidence rules themselves, have clarified the nature and extent of the inquiry judges must conduct into the reasonable reliance upon facts and data, and into the inferential steps leading to a conclusion.  And yet, many judges resist, and offer up excuses and dodges for shirking their gatekeeping obligations.  See generally David E. Bernstein, “The Misbegotten Judicial Resistance to the Daubert Revolution,” 89 Notre Dame L. Rev. 27 (2013).

There is a courtroom in New Jersey, in which gatekeeping is taken seriously from beginning to end.  There is at least one trial judge who encourages and even demands that the expert witnesses appear and explain their methodologies and actually show their methodological compliance.  Judge Johnson first distinguished himself in In re Accutane, No. 271(MCL), 2015 WL 753674, 2015 BL 59277 (N.J.Super. Law Div. Atlantic Cty. Feb. 20, 2015).[1] And more recently, in two ovarian cancer cases, Judge Johnson dusted two expert witnesses, who thought they could claim their turn in the witness chair by virtue of their credentials and some rather glib hand waving. Judge Johnson conducted the New Jersey analogue of a Federal Rule of Evidence 104(a) Daubert hearing, as required by the New Jersey Supreme Court’s decision in Kemp v. The State of New Jersey, 174 N.J. 412 (2002). The result was disastrous for the two expert witnesses who opined that use of talcum powder by women causes ovarian cancer. Carl v. Johnson & Johnson, No. ATL-L-6546-14, 2016 WL 4580145 (N.J. Super. Ct. Law Div., Atl. Cty., Sept. 2, 2016) [cited as Carl].

Judge Johnson obviously had a good epidemiology teacher in Professor Stephen Goodman, who testified in the Accutane case.  Against this standard, it is easy to see how the plaintiffs’ talc expert witnesses, Drs. Daniel Cramer and Dr. Graham Colditz, fell “significantly” short. After presiding over seven days of court hearings, and reviewing extensive party submissions, including the actual studies relied upon by the expert witnesses and the parties, Judge Johnson made no secret of his disappointment with the lack of rigor in the analyses proffered by Cramer and Colditz:

“Throughout these proceedings the court was disappointed in the scope of Plaintiffs’ presentation; it almost appeared as if counsel wished the court to wear blinders. Plaintiffs’ two principal witnesses on causation, Dr. Daniel Cramer and Dr. Graham Colditz, were generally dismissive of anything but epidemiological studies, and within that discipline of scientific investigation they confined their analyses to evidence derived only from small retrospective case-control studies. Both witnesses looked askance upon the three large cohort studies presented by Defendants. As confirmed by studies listed at Appendices A and B, the participants in the three large cohort studies totaled 191,090 while those case-control studies advanced by Plaintiffs’ witnesses, and which were the ones utilized in the two meta-analyses performed by Langseth and Terry, total 18,384 participants. As these proceedings drew to a close, two words reverberated in the court’s thinking:

“narrow and shallow.” It was almost as if counsel and the expert witnesses were saying, Look at this, and forget everything else science has to teach as.

Carl at *12.

Judge Johnson did what for so many judges is unthinkable; he looked behind the curtain put up by highly credentialed Oz expert witnesses in his courtroom. What he found was unexplained, unjustified selectivity in their reliance upon some but not all the available data, and glib conclusions that gloss over significant limits in the resolving power of the available epidemiologic studies. Judge Johnson was particularly unsparing of Graham Colditz, a capable scientist, who deviated from the standards he set for himself in the work he had published in the scientific community:

“Dr. Graham Colditz is a brilliant scientist and a dazzling witness. His vocal inflection, cadence, and adroit use of histrionics are extremely effective. Dr. Colditz’s reputation for his breadth of knowledge about cancer and the esteem in which he is held by his peers is well deserved. Yet, at times, it seemed that issues raised in these proceedings, and the questions posed to him, were a bit mundane for a scientist of his caliber.”

Carl at *15. Dr. Colditz and the plaintiffs’ cause were not helped by Dr. Colditz’s own previous publications of studies and reviews that failed to support any “substantial association between perineal talc use and ovarian cancer risk overall,” and failed to conclude that talc was even a “risk factor” for ovarian cancer.  Carl at *18.

Relative Risk Size

Many courts have fumbled their handling of the issue whether applicable relative risks must exceed two before fact finders may infer specific causation between claimed exposures and specific diseases. There certainly can be causal associations that involve relative risks between 1.0, up to and including 2.0.  Eliminating validity concerns may be more difficult with such smaller relative risks, but there is nothing theoretically insuperable about having a causal association based upon such small relative risks. Judge Johnson apparently saw the diversity of opinions on this relative risk issue, many of which opinions are stridently maintained, and thoroughly fallacious.

Judge Johnson ultimately did not base his decision, with respect to general or specific causation, on the magnitude of relative risk, or the covering Bradford Hill factor of “strength of association.” Dr. Cramer appropriately acknowledged that his meta-analysis result, of an odds ratio of 1.29 was “weak,” Carl at *19, and Judge Johnson was critical of Dr. Colditz for failing to address the lack of strength of the association, and for engaging in a constant refrain that the association was “significant,” which is a precision not a size estimate for the measurement. Carl at *17.

Aware of the difficulty that New Jersey appellate courts have had with the issues surrounding relative risks greater than two, Judge Johnson was realistic to steer clear of any specific judicial reliance on the small size of the relative risk.  His Honor’s prudence is unfortunate however because ultimately small relative risks, even assuming that general causation is established, do nothing to support specific causation.  Indeed, relative risks of 1.29 (and odds ratios generally overstate the size of the underlying relative risk) would on a stochastic model support the conclusion that specific causation was less than 50% probable.  Critics have pointed out that risk may not be stochastically distributed, which is a great point, except that

(1) plaintiffs often have no idea how the risk, if real, is distributed in the observed sample, and

(2) the upshot of the point is that even for relative risks greater than 2.0, there is no warrant for inferring specific causation in a given case.

Judge Johnson did wade into the relative risk waters by noting that when relative risks were “significantly” less than two, establishing biological plausibility became essential.  Carl at *11.  This pronouncement is muddled on at least two fronts.  First, the relative risk scale is a continuum, and there is no standard reference for what relative risks greater than 1.0 are “significantly” less than 2.0.  Presumably, Judge Johnson thought that 1.29 was in the “significantly less than 2.0” range, but he did not say so; nor did he cite a source that supported this assessment. Perhaps he was suggesting that the upper bound of some meta-analysis was less than two. Second, and more troubling, the claim that biological plausibility becomes “essential” in the face of small relative risks is also unsupported. Judge Johnson does not cite any support for this claim, and I am not aware of any.  Elsewhere in his opinion, Judge Johnson noted that

“When a scientific rationale doesn’t exist to explain logically the biological mechanism by which an agent causes a disease, courts may consider epidemiologic studies as an alternate [sic] means of proving general causation.”

Carl at *8. So it seems that biological plausibility is not essential after all.

This glitch in the Carl opinion is likely of no lasting consequence, however, because epidemiologists are rarely at a loss to posit some biologically plausible mechanism. As the Dictionary of Epidemiology explains the matter:

“The causal consideration that an observed, potentially causal association between an exposure and a health outcome may plausibly be attributed to causation on the basis of existing biomedical and epidemiological knowledge. On a schematic continuum including possible, plausible, compatible, and coherent, the term plausible is not a demanding or stringent requirement, given the many biological mechanisms that often can be hypothesized to underlie clinical and epidemiological observations; hence, in assessing causality, it may be logically more appropriate to require coherence (biological as well as clinical and epidemiological). Plausibility should hence be used cautiously, since it could impede development or acceptance of new knowledge that does not fit existing biological evidence, pathophysiological reasoning, or other evidence.”

Miquel Porta, et al., eds., “Biological plausibility,” in A Dictionary of Epidemiology at 24 (6th ed. 2014). Most capable epidemiologists have thought up half a dozen biologically plausible mechanisms each morning before they have had their first cup of coffee. But the most compelling reason that this judicial hiccup is inconsequential is that the plaintiffs’ expert witnesses’ postulated mechanism, inflammation, was demonstrably absent in the tissue of the specific plaintiffs.  Carl at *13. The glib invocation of “inflammation” would seem bound to fail even as the most liberal test of plausibility when talc has anti-cancer properties that result from its ability to inhibit new blood vessel formation, a necessity of solid tumor growth, and the completely unexplained selectivity for ovarian tissue to the postulated effect, which leaves vaginal, endometrial, or fallopian tissues unaffected. Carl at *13-14. On at least two occasions, the United States Food and Drug Administration rejected “Citizen Petitions” for ovarian cancer warnings on talc products, advanced by the dubious Samuel S. Epstein for the Cancer Prevention Coalition, in large measure because of Epstein’s undue selectivity in citing epidemiologic studies and because a “cogent biological mechanism by which talc might lead to ovarian cancer is lacking… .” Carl at *15, citing Stephen M. Musser, Directory FDA Director, Letter Denying Citizens’ Petition (April 1, 2014).

Large Studies

Judge Johnson quoted the Reference Manual on Scientific Evidence (3d ed.  2011) for his suggestion that establishing causation requires large studies.  The quoted language, however, really does not bear on his suggestion:

“Common sense leads one to believe that a large enough sample of individuals must be studied if the study is to identify a relationship between exposure to an agent and disease that truly exists. Common sense also suggests that by enlarging the sample size (the size of the study group), researchers can form a more accurate conclusion and reduce the chance of random error in their results…With large numbers, the outcome of test is less likely to be influenced by random error, and the researcher would have greater confidence in the inferences drawn from the data.”

Reference Manual at page 576.  What the Reference Manual simply calls for studies with “large enough” samples.  How large is large enough is a variable that depends upon the magnitude of the association to be detected, the length of follow up, and the base rate or incidence of the outcome of interest. As far as “common sense,” goes, the Reference Manual is correct only insofar as larger is better with respect to sampling error.  Increasing sample size does nothing to address internal or external validity of studies, and may lead to erroneous interpretations by allowing results to achieve statistical significance at predetermined levels, when the observed associations result from bias or confounding, and not from any underlying relationship between exposure and disease outcome.

There is a more disturbing implication in Judge Johnson’s criticism of Graham Colditz for relying upon the smaller number of subjects in the case-control studies than are found in the available cohort studies. Ovarian cancer is a relatively rare cancer (compared with breast and colon cancer), and case-control studies are more efficient at assessing increased risk than are cohort studies for a rare outcome.  The number of cases in a case-control study represents an implied population many times larger than the number of actual cases in a case-control study.  If Judge Johnson had looked at the width of the confidence intervals for the “small” case-control studies, and compared those widths to the interval widths of the cohort studies, he would have seen that “smaller” case-control studies (fewer cases, as well as fewer total subjects) can generate more statistical precision than the larger cohort studies (with many more cohort and control subjects).  A more useful comparison would have been to the number of actual ovarian cancer cases in the meta-analyzed case-control studies with the number of actual ovarian cancer cases in the cohort studies. On this comparison, the cohort studies might not fare so well.

The size of the cohort for a rare outcome is thus fairly meaningless in terms of the statistical precision generated.  Smaller case-control studies will likely have much more power, and that should be reflected in the confidence intervals of the respective studies.

The issue, as I understand the talc litigation, is not size of the case-control versus cohort studies, but rather their analytical resolving power.  Case-control studies for this sort of exposure and outcome will be plagued by recall and other biases, as well as difficulty in selecting the right control group.  And the odds ratio will tend to overestimate the relative risk, in both directions.  Cohort studies, with good, pre-morbid exposure assessments, would thus be much more rigorous and accurate in estimating the true rate ratios. In the final analysis, Judge Johnson was correct to be critical of Graham Colditz for dismissing the cohort studies, but his rationale for this criticism was, in a few places, confused and confusing. There was nothing subtle about the analytical gaps, ipse dixits, and cherry picking shown by these plaintiffs’ expert witnesses.

[1] SeeJohnson of Accutane – Keeping the Gate in the Garden State” (Mar. 28, 2015).

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