TORTINI

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

A Black Swan Case – Bayesian Analysis on Medical Causation

March 15th, 2014

Last month, I posted about an article that Professor Greenland wrote several years ago about his experience as a plaintiffs’ expert witness in a fenfluramine case. “The Infrequency of Bayesian Analyses in Non-Forensic Court Decisions (Feb. 16, 2014).” Greenland chided a defense expert for having declared that Bayesian analyses are rarely or never used in analyzing clinical trials or in assessments of pharmaco-epidemiologic data.  Greenland’s accusation of ludicrousness appeared mostly to blow back on him, but his stridency for Bayesian analyses did raise the question, whether such analyses have ever moved beyond random-match probability analyses in forensic evidence (DNA, fingerprint, paternity, etc.) or in screening and profiling cases.  I searched Google Scholar and Westlaw for counter-examples and found none, but I did solicit references to “Black Swan” cases. Shortly after I posted about the infrequency of Bayesian analyses, I came across a website that was dedicated to collecting legal citations of cases in which Bayesian analyses were important, but this website appeared to confirm my initial research.

Some months ago, Professor Brian Baigrie, of the Jackman Humanities Institute, at the University of Toronto, invited me to attend a meeting of an Institute working group on The Reliability of Evidence in Science and the Law.  The Institute fosters interdisciplinary scholarship, and this particular working group has a mission statement close to my interests:

The object of this series of workshops is to formulate a clear set of markers governing the reliability of evidence in the life sciences. The notion of evidence is a staple in epistemology and the philosophy of science; the notion of this group will be the way the notion of ‘evidence’ is understood in scientific contexts, especially in the life sciences, and in judicial form as something that ensures the objectivity of scientific results and the institutions that produce these results.

The Reliability of Evidence in Science and the Law. The faculty on the working group represent disciplines of medicine (Andrew Baines), philosophy (James R. Brown, Brian Baigrie), and law (Helena Likwornik, Hamish Stewart), with graduate students in the environmental science (Amy Lemay), history & philosophy of science and technology (Karolyn Koestler, Gwyndaf Garbutt ), and computer science (Maya Kovats).

Coincidentally, in preparation for the meeting, Professor Baigrie sent me links to a Canadian case, Goodman v. Viljoen, which turned out to be a black swan case! The trial court’s decision, in this medical malpractice case focused mostly on a disputed claim of medical causation, in which the plaintiffs’ expert witnesses sponsored a Bayesian analysis of the available epidemiologic evidence; the defense experts maintained that causation was not shown, and they countered with the unreliability of the proffered Bayesian analysis. The trial court resolved the causation dispute in favor of the plaintiffs, and their witnesses’ Bayesian approach. Goodman v. Viljoen, 2011 ONSC 821 (CanLII), aff’d, 2012 ONCA 896 (CanLII).  The Court of Appeals’ affirmance was issued over a lengthy, thoughtful dissent. The Canadian Supreme Court denied leave to appeal.

Goodman was a medical practice case. Mrs. Goodman alleged that her obstetrician deviated from the standard of care by failing to prescribe corticosteroids sufficiently early in advance of delivery to avoid or diminish the risk of cerebral palsy in her twins.  Damages were stipulated, and the breach of duty turned on a claim that Mrs. Goodman, in distress, called her obstetrician.  Given the decade that passed between the event and the lawsuit, the obstetrician was unable to document a response.  Duty and breach were disputed, but were not the focus of the trial.

The medical causation claim, in Goodman, turned upon a claim that the phone call to the obstetrician should have led to an earlier admission to the hospital, and the administration of antenatal corticosteroids.  According to the plaintiffs, the corticosteroids would have, more probably than not, prevented the twins from developing cerebral palsy, or would have diminished the severity of their condition.  The plaintiffs’ expert witnesses relied upon studies that suggested a 40% reduction and risk, and a probabilistic argument that they could infer from this risk ratio that the plaintiffs’ condition would have been avoided.  The case thus raises the issue whether evidence of risk can substitute for evidence of causation.  The Canadian court held that risk sufficed, and it went further, contrary to the majority of courts in the United States, to hold that a 40% reduction in risk sufficed to satisfy the more-likely-than-not standard.  See, e.g., Samaan v. St. Joseph Hosp., 670 F.3d 21 (1st Cir. 2012) (excluding expert witness testimony based upon risk ratios too small to support opinion that failure to administer intravenous tissue plasminogen activator (t-PA) to a patient caused serious stroke sequelae); see also “Federal Rule of Evidence 702 Requires Perscrutations — Samaan v. St. Joseph Hospital (2012)” (Feb. 4, 2012).

The Goodman courts, including the dissenting justice on the Ontario Court of Appeals, wrestled with a range of issues that warrant further consideration.  Here are some that come to mind from my preliminary read of the opinions:

1. Does evidence of risk suffice to show causation in a particular case?

2. If evidence of risk can show causation in a particular case, are there requirements that the magnitude of risk be quantified and of a sufficient magnitude to support the inference of causation in a particular case?

3. The judges and lawyers spoke of scientific “proof.”  When, if ever, is it appropriate to speak of scientific proof of a medical causal association?

4. Did the judges incorrectly dichotomize legal and scientific standards of causation?

5. Did the judges, by rejecting the need for “conclusive proof,” fail to articulate a meaningful standard for scientific evidence in any context, including judicial contexts?

6. What exactly does the “the balance of probabilities” mean, especially in the face of non-quantitative evidence?

7. What is the relationship between “but for” and “substantial factor” standards of causation?

8. Can judges ever manage to define “statistical significance” correctly?

9. What is the role of “common sense” in drawing inferences by judges and expert witnesses in biological causal reasoning?  Is it really a matter of common sense that if a drug did not fully avert the onset of a disease, it would surely have led to a less severe case of the disease?

10. What is the difference between “effect size” and the measure of random or sampling error?

11. Is scientific certainty really a matter of being 95% certain, or is this just another manifestation of the transposition fallacy?

12. Are Bayesian analyses acceptable in judicial settings, and if so, what information about prior probabilities must be documented before posterior probabilities can be given by expert witnesses and accepted by courts?

13. Are secular or ecological trends sufficiently reliable data for expert witnesses to rely upon in court proceedings?

14. Is the ability to identify biological plausibility sufficient to excuse the lack of statistical significance and other factors that are typically needed to support the causality of a putative association?

15. What are the indicia of reliability of meta-analyses used in judicial proceedings?

16. Should courts give full citations to scientific articles that are heavily relied upon as part of the requirement that they publicly explain and justify their decisions?

These are some of the questions that come to mind from my first read of the Goodman case.  The trial judge attempted to explain her decision in a fairly lengthy opinion. Unfortunately, the two judges, of the Ontario Court of Appeals, who voted to affirm, did not write at length. Justice Doherty wrote a thoughtful dissent, but the Supreme Court denied leave to appeal.  Many of the issues are not fully understandable from the opinions, but I hope to be able to read the underlying testimony before commenting.

Thanks to Professor Baigrie for the reference to this case.

Judicial Notice of Untruths

March 3rd, 2014

Judicial notice is a procedure for admitting facts the truth of which are beyond dispute. A special kind of magically thinking occurs when judges take judicial notice of falsehoods, myths, or lies.

In the federal judicial system, Federal Rule of Evidence 201 addresses judicial notice of adjudicative facts, and provides:

(b) Kinds of Facts That May Be Judicially Noticed. The court may judicially notice a fact that is not subject to reasonable dispute because it:

(1) is generally known within the trial court’s territorial jurisdiction; or

(2) can be accurately and readily determined from sources whose accuracy cannot reasonably be questioned.

Procedurally, Rule 201 provides that a court must take judicial upon the request of a party who has supplied any needed basis for the fact to be noticed.  A court may take notice sua sponte.  Rule 201(c)(1), (2).

In the Chantix litigation, counsel for Pfizer challenged plaintiffs’ expert witness, Curt Furberg, on Rule 702 grounds.  According the MDL judge, the Hon. Inge Prytz Johnson, Pfizer asserted that Furberg’s proferred testimony because the FDA approved Chantix as safe and effective. In re Chantix (Varenicline) Prods. Liab. Litig., 889 F. Supp. 2d 1272, 1285 n.8 (N.D. Ala. 2012).  Citing no authority or text, Judge Johnson announced that “[a]pproval by the FDA is not evidence of the safety of a medication.” Id.

To be sure, safety issue can sometimes arise after initial approval, but before the FDA or the manufacturer and sponsor of the medication can react to the new safety data.  The sweeping statement, however, that the FDA’s approval is not any evidence of safety seems bereft of factual support and common sense.

Judge Johnson went on, however, to invent supporting evidence out of thin air:

“The court takes judicial notice of such things as that at one time, thalidomide was used for morning sickness in pregnant women. Unfortunately, 10,000 children were born with birth defects from it before it was banned. And 50  years elapsed before doctors understood why thalidomide caused limbs to disappear. See e.g. http://www.nytimes.com/2010/03/16/science/16limb.html?pagewanted=all. Similarly, the fact that the FDA at one time approved Vioxx did not prevent the same being removed from the market due to growing concerns that it increased the risk of heart attacks and strokes. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm103420.htm. Hence, initial approval by the FDA is not proof of the safety of a medication.”

The point about the FDA’s approval not constituting evidence of safety may simply be sloppy writing and reasoning.  In the quote above, perhaps Her Honor merely meant to say that initial approval is not evidence that a medication is safe in view of later obtained data that were not available to the FDA on its review of the new drug application.  If so, fair enough, but the sweeping statement that the initial approval is no evidence of safety ignores the considerable time, cost, and energy that goes into the FDA’s review of safety before agency approves marketing.

More egregious, however, is Judge Johnson’s taking judicial notice of the marketing of thalidomide as though it had some relevancy and probative value for her claim about the inefficacy of the FDA’s safety reviews.[1]  Consider the recent review of the FDA’s handling of thalidomide by Margaret Hamburg, M.D., Commissioner of the U. S. Food and Drug Administration:

“Fifty years ago, the vigilance of FDA medical officer Dr. Frances Kelsey prevented a public health tragedy of enormous proportion by ensuring that the sedative thalidomide was never approved in the United States.  As many remember, in the early 1960’s, reports were coming in from around the world of countless women who were giving birth to children with extremely deformed limbs and other severe birth defects.  They had taken thalidomide. Although it was being used in many countries, Dr. Kelsey discovered that it hadn’t even been tested on pregnant animals.”

Margaret Hamburg, “50 Years after Thalidomide: Why Regulation Matters” (Feb. 7, 2012).

Judge Johnson took judicial notice of a non-fact. The FDA never approved thalidomide for use in the United States, back in the 1950s or 1960s.[2]



[1] Judge Johnson’s fantastical history of the FDA was recently cited by plaintiffs’ counsel in the Zoloft birth defects litigation.  See Plaintiffs’ Opposition to Defendants’ Motion to Exclude the Testimony of Anick Berard, Ph.D., at 13 (Filed Feb. 24, 2014), in In re Zoloft (sertraline hydrochloride) Prods. Liab. Litig., Case 2:12-md-02342-CMR Document 713.

[2] Judge Johnson’s errant history may have resulted from her European perspective of the thalidomide tragedy.  Judge Inge Prytz Johnson immigrated from Denmark, where she was born and educated. She became a U.S. citizen in 1978, and a state court judge one year later.  In 1998, she was nominated by President Clinton to the Northern District of Alabama.  In October 2012, Judge Johnson assumed senior status. See Kent Faulk, “U.S. District Judge Inge Johnson goes into semi-retirement” (Oct. 19, 2012) (quoting Judge Johnson as saying that “One thing I like about my job is I don’t have to take sides.”)

“Judges and other lawyers must learn how to deal with scientific evidence and inference.”

March 1st, 2014

Late last year, a panel of 7th Circuit reversed an Administrative Law Judge (ALJ) who had upheld a citation and fine against Caterpillar Logistics, Inc. (Cat).  The panel, in a wonderfully succinct, but meaty decision by Judge Easterbrook, wrote of the importance of judges’ and lawyers’ learning to deal with scientific and statistical evidence. Caterpillar Logistics, Inc. v. Perez, 737 F.3d 1117 (7th Cir. 2013)

Pseudonymous MK, a worker in Cat’s packing department, developed epidcondylitis (tennis elbow).  Id. at 1118. OSHA regulations require employers to report injuries  “the work environment either caused or contributed to the resulting condition”. 29 C.F.R. § 1904.5(a). MK’s work required her to remove items from containers and place items in shipping cartons. The work was repetitive, but MK acknowledged that the work involved little or no impact or force.  Apparently, Cat gave some rather careful consideration to whether MK’s epidcondylitis was work related; it assembled a panel of three specialists in musculoskeletal disorders and two generalists to consider the matter.  The panel, relying upon NIOSH and AMA guidelines, rejected MK’s claim of work relatedness.  Both the NIOSH and the AMA guidelines conclude that repetitive motion in the absence of weight or impact does not cause epicondylitis. Id.

MK called an expert witness, Dr. Robert Harrison, a clinical professor of medicine, at the University of California, San Francisco.  Id. at 1118-1119.  Harrison unequivocally attributed MK’s condition to her work at Cat, but he failed to explain why no one else in Cat’s packing department ever developed the condition.  Id. at 1119.

Harrison acknowledged that epidemiologic evidence could confirm his opinion, but he dismissed such evidence as being able to disconfirm his opinion.  The ALJ echoed Dr. Harrison in holding epidemiologic evidence to be irrelevant:

“none of these [other] people are [sic] MK. Similar to the concept of the ‘eggshell skull’ plaintiff in civil litigation, you take your workers as they are.”

Id. at 1119-20, citing ALJ, at 2012 OSAHRC LEXIS 118 at *32.

Judge Easterbrook found this attempt to disqualify any opposing evidence to lie beyond the pale:

“Judges and other lawyers must learn how to deal with scientific evidence and inference.”

Id. (citing Jackson v. Pollion, 733 F.3d 786 (7th Cir. 2013).

Judge Easterbrook called out the ALJ for misunderstanding the nature of epidemiology and the role of statistics, in the examination of causation of health outcomes that have a baseline incidence or prevalence in the population:

“The way to test whether Harrison is correct is to look at data from thousands of workers in hundreds of workplaces—or at least to look at data about hundreds of worker-years in Caterpillar’s own workplace. Any given worker may have idiosyncratic susceptibility, though there’s no evidence that MK does. But the antecedent question is whether Harrison’s framework is sound, and short of new discoveries about human physiology only statistical analysis will reveal the answer. Any large sample of workers will contain people with idiosyncratic susceptibilities; the Law of Large Numbers ensures that their experience is accounted for. If studies of large numbers of workers show that the incidence of epicondylitis on jobs that entail repetitive motion but not force is no higher than for people who do not work in jobs requiring repetitive motion, then Harrison’s view has been refuted.”

Id. at 1120.

Judge Easterbrook acknowledged that Cat’s workplace evidence may have been a sample too small from which to draw a valid statistical inference, given the low base rate of epicondylitis in the general population.  Dr. Harrison’s and the ALJ’s stubborn refusal, however, to consider any disconfirming evidence, obviating the need to consider sample size and statistical power issues.

Finally,  Judge Easterbrook chastised the ALJ for dismissing Cat’s experience as irrelevant because many other employers will not have sufficient workforces or record keeping to offer similar evidence.  In Judge Easterbrook’s words:

“This is irrational. If the camera in a police car captures the events of a highspeed chase, the judiciary would not ignore that video just because other police cars lack cameras; likewise, if the police record an interrogation, courts will consider that information rather than wait for the day when all interrogations are recorded.”

Id. This decision illustrates why some commentators at places such as the Center for Progressive Reform get their knickers in a knot over the prospect of applying the strictures of Rule 702 to agency fact finding; they know it will make a difference.

As for the “idiosyncratic gambit,” this argument is made all too frequently in tort cases, with similar lack of predicate.  Plaintiffs claim that there may be a genetic or epigenetic susceptibility in a very small subset of the population, and that epidemiologic studies may miss this small, sequestered risk.  Right, and the light in the refrigerator may stay on when you close the door.  Prove it!

Pennsylvania Superior Court Takes The Bite Out of Fixodent Claims

December 12th, 2013

In the spring of 2012, Judge Sandra Mazer Moss granted summary judgment to Proctor & Gamble, after excluding, on Frye grounds, plaintiff’s expert witnesses who opined that plaintiff suffered zinc neurotoxicity from his use of FixodentJacoby v. Rite Aid Corp., 2012 Phila. Ct. Com. Pl. LEXIS 208 (2012).  SeePhiladelphia Plaintiff’s Claims Against Fixodent Prove Toothless” (May 2, 2012).  Judge Moss’s exclusion of plaintiff’s expert witnesses involved a careful analysis of the evasive, hand-waving tactics of the witnesses.  Among the plaintiff’s team of expert witnesses was Dr. Martyn Smith, the chief hand waver and obscurantist in Milward v. Acuity Specialty Products Group, Inc., 664 F.Supp. 2d 137 (D. Mass. 2009), rev’d, 639 F.3d 11 (1st Cir. 2011), cert. denied, U.S. Steel Corp. v. Milward, ___ U.S. ___, 2012 WL 33303 (2012).

On Monday, December 9, 2013, after a careful review, the Pennsylvania Superior Court affirmed summary judgment for Proctor & Gamble in the Jacoby case. Jacoby v. Rite Aid Corp., Pa. Super. Ct. No. 1508 EDA 2012 (Dec. 9, 2013) [Slip op.]  The Superior Court panel, consisting of Judges Stevens, Lazarus, and Colville, largely adopted Judge Moss’s analysis and affirmed in a signed, but unpublished, opinion by Judge Lazarus. 

Like Judge Moss before them, the Panel saw through the attempt to pass off “Weight of the Evidence” (WOE) and “Totality of the Evidence” (TOE) as scientific methodologies.  The witnesses, Martyn Smith and others, failed to specify what evidence they weighed, how they weighed the evidence, and what the weights supposedly were.  Another expert witness vaguely pointed to the “Naranjo scale” in support of interpreting case reports to show causal association, but this scale was similarly incompetent other than as a crude “plausibility” scale for assessing case reports.

The Superior Court’s decision in Jacoby is noteworthy on several important issues. There was no material issue as to whether zinc at some dose and duration of exposure can cause neuropathies.  The Court saw, however, that the important issue was whether zinc in the form, dose, and duration ingested by plaintiff can cause the outcome he experienced, and whether his exposure to zinc in Fix-o-dent actually caused his alleged injury.  The Superior Court re-affirmed Pennsylvania’s case law that makes extrapolation from different doses, different durations, and different biological circumstances, a “novel” claim that is subject to the gatekeeping by the so-called Frye standard. Slip op. at 11.

The Superior Court’s opinion astutely observed that the issue was not whether WOE and TOE are accepted scientific methodologies, but whether expert witness Martyn Smith can “evade a reasoned Frye inquiry merely by making reference to accepted methods in the abstract.”  Id. at 12 (citing Betz, at 58).  When pressed, Martyn Smith’s invocation of WOE amounted to little more than a distortion and abridgment of the Bradford Hill factors.  The Superior Court recognized, however, that the Bradford Hill guidelines provide an evaluative process to consider whether an association, after first being shown to be clear cut and not attributable to chance, is causal or spurious.  Id. at 13.  As Bradford Hill postulated the question that arises before his famous nine factors come into the analysis:

“Disregarding then any such problem in semantics we have this situation. Our observations reveal an association between two variables, perfectly clear-cut and beyond what we would care to attribute to the play of chance. What aspects of that association should we especially consider before deciding that the most likely interpretation of it is causation?”

Austin Bradford Hill, “The Environment and Disease: Association or Causation?” 58 Proc. Royal Soc’y Med. 295, 295 (1965) (emphasis added).

In this case, Smith never got off the dime with his evasive tactics.  He did not identify a quantified association that could be assessed for the play of random variation, or bias and confounding.  Smith tried to suggest that a mere possibility of an association was sufficient to invoke the Bradford Hill guidelines, but the Superior Court rejected this attempt to invent a new-age scientific method. Slip op. at 13.

The Superior Court acknowledged that the scientific literature describes WOE as varying from nothing more than “seat-of-the-pants qualitative assessment” to “aggregating diverse modalities.”  Id. at 14.  In Smith’s hands, WOE was little more than a personal, subjective opinion, an ipse dixit dressed as a scientific opinion.  Smith never defined his WOE approach, and the other witnesses never defined their TOE approach.  The plaintiffs’ witnesses in Jacoby failed to offer an accepted methodology when they failed to identify the forms of evidence they considered, and how they went about weighing the evidence upon which they had relied.  Id. at 15.

In a brief discussion, the Panel also embraced another basic evidentiary principle to dismiss a common tactic in specious claiming. The plaintiffs’ challenged defendants’ pharmokinetic study and tried to suggest that their deconstruction counted as affirmative evidence to support their own theory of biological fate and distribution. Id. at 16.  The Superior Court saw through the ruse; the plaintiffs had not created affirmative evidence for their theory by arguing that the defendants’ study was flawed. 

The Superior Court squarely confronted the limitations and inadequacy of relying upon descriptive, anecdotal case reports. Case reports provide a narrative and temporal history of events with respect to exposure and outcome, but they cannot fully account for confounding by known and unknown factors.  Case reports represent post hoc assessments that were not planned, and therefore lack data that would permit distinguishing coincidence from causality.  Id. at 17 (citing Dr. Lorene Nelson’s report).  See In re Denture Cream Prods. Liab. Litig., 795 F. Supp. 2d 1345 (S.D. Fla.2011).

Proctor & Gamble had the good fortunate to have obtained a good ruling in the MDL litigation in the Southern District of Florida, which no doubt helped focus the gatekeeping process in Pennsylvania state court. Unfortunately, the Superior Court Panel chose not to publish its decision.  This decision is regrettable for its inconsistency with the transparency and due process expected of all courts.  See Erica Weisgerber, “Unpublished Opinions: A Convenient Means to an Unconstitutional End,” 97 Georgetown L.J. 621 (2009).

Pharmacovigilantism – Avandia Litigation

November 27th, 2013

Six and one-half years ago, I gave a presentation on the then newly emerging controversy over Avandia (rosiglitazone).  Plaintiffs’ counsel Vance Andrus chaired the program, Mealey’s™ Avandia Litigation Conference, in Chicago on July 13, 2007.  Vance was a gracious host despite my skepticism about the potential for plaintiffs to cash in on their use of Avandia.

Despite Vance’s best efforts, the program was one of those lopsided affairs, and I was the only presenter who came prepared to address the scientific evidence from a skeptical perspective.  The remaining presenters were mostly cheerleaders for their declaration of war against GlaxoSmithKline over claims of heart attack and stroke from the use of Avandia.

This week, a Food and Drug Administration announcement sent me back to my presentation slides, which were provocatively titled “Pharmacovigilantism and Avandia.” Dr. Steven Nissen had published a meta-analysis in the New England Journal of Medicine in May 2007, and it had all the appearances of a contrived effort to embarrass GSK. See Steven E. Nissen, M.D., and Kathy Wolski, M.P.H., “Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes,” 356 New Engl. J. Med. 2457 (2007).  A few weeks later, Dr. George Diamond published a thorough debunking of the Nissen meta-analysis, by showing that the statistically significant result in Nissen’s meta-analysis could be achieved only by choosing an inappropriate meta-analytic method.  Any other choice resulted in a result that lacked statistical significance for the rate of heart attack among patients taking Avandia.

Litigation, of course, followed and the Rule 702 hearings and decision resulted in a serious abridgement of the scientific process.  The federal MDL trial judge denied GSK’s motions to exclude plaintiffs’ causation witnesses in an opinion that has become a model for Rule 702 avoidance.  In re Avandia Marketing, Sales Practices and Product Liability Litigation, 2011 WL 13576, *12 (E.D. Pa. 2011) (Rufe, J.).  SeeLearning to Embrace Flawed Evidence – The Avandia MDL’s Daubert Opinion” (Jan. 10, 2011)

This week, without much fanfare, the FDA announced that maybe the evidence supporting the claims that Avandia causes heart attacks is not so strong, after all.  SeeFDA Drug Safety Communication: FDA requires removal of some prescribing and dispensing restrictions for rosiglitazone-containing diabetes medicines” (Nov. 25, 2011).  The Avandia MDL stands out as an expensive, negligent rush to judgment; a case more of phamacovigilantism than of pharmacovigilance.

Bendectin, Diclegis & The Philosophy of Science

October 26th, 2013

In April of this year, the United States Food and Drug Administration (FDA) approved Diclegis, a combination of doxylamine succinate and pyridoxine hydrochloride for sale in the United States, for pregnant women experiencing nausea and vomiting. See FDA News Release, “FDA approves Diclegis for pregnant women experiencing nausea and vomiting,” (April 8, 2013). The return of this drug to the United States market was held up as a triumph of science over the will of the lawsuit industry. See Gideon Koren, “The Return to the USA of the Doxylamine-Pyridoxine Delayed Release Combination (Diclegis®) for Morning Sickness — A New Morning for American Women,” 20 J. Popul. Ther. Clin. Pharmacol. e161 (2013).

The sponsor of the drug, Duchesnay USA, wisely did not use the medication’s former name, Bendectin, which was the victim of a litigation industry jihad in the late 1970s through the mid-1990s. The plaintiffs’ lawyers’ war against Bendectin and its United States manufacturer is chronicled in two book-length accounts, and hundreds of articles. See Joseph Sanders, Bendectin on Trial: A Study of Mass Tort Litigation (Ann Arbor 1998); Michael D. Green, Bendectin and Birth Defects: The Challenges of Mass Toxic Substances Litigation (Philadelphia 1996).

As recently approved by the FDA, Declegis is categorized as “Pregnancy Category A,” which means that it is medication indicated for use in pregnant women. Most drugs are not tested in pregnant women in randomized clinical trials for obvious ethical and practical reasons. Perhaps one of the good things that came out of the Bendectin litigation wars was that Bendectin became one of the most intensely studied medications available for pregnant women. Another good thing was the achievement of evidence-based standards for expert witness opinion testimony in federal court. See David Bernstein, “Bendectin is Back” (April 9, 2013).

According to FDA regulations, Category A is defined:

“(1) Pregnancy category A. If adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of a risk in later trimesters), the labeling must state: ‘Pregnancy Category A. Studies in pregnant women have not shown that (name of drug) increases the risk of fetal abnormalities if administered during the first (second, third, or all) trimester(s) of pregnancy. If this drug is used during pregnancy, the possibility of fetal harm appears remote. Because studies cannot rule out the possibility of harm, however, (name of drug) should be used during pregnancy only if clearly needed.’ The labeling must also contain a description of the human studies. If animal reproduction studies are also available and they fail to demonstrate a risk to the fetus, the labeling must also state: ‘Reproduction studies have been performed in (kinds of animal(s)) at doses up to (x) times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to (name of drug).’ The labeling must also contain a description of available data on the effect of the drug on the later growth, development, and functional maturation of the child.

21 CFR § 201.57 (c)(9)(i)(A)(1) (April 2012).

A Litmus Test for Philosophy of Science?

The inability to discriminate between valid and invalid science should be a disqualifying characteristic in a putative philosopher of science, or a putative expert, for that matter. Professor Susan Haack, whose writings provide both insight and confusion on the role of science in the law, revealed her robust biases and prejudices in commenting upon the Bendectin litigation. These revelations should raise red flags about her objectivity in commenting on the legal process. See Susan Haack, “Irreconcilable Differences? The Troubled Marriage of Science and Law,” 72 Law & Contemporary Problems 1 (2009).

Haack’s paper on the marital discord was based upon her presentation at the Fourth Coronado Conference, organized by SKAPP (The Project on Scientific Knowledge and Public Policy), an ideological group dedicated to opening the courthouse doors to every quackacademic theory, and shadily funded by the litigation industry of plaintiffs’ lawyers from their left-over spoils from the silicone breast implant litigation. See SKAPP A LOT (April 30, 2010); “Haacking at the Truth – Part Two” (Oct. 31, 2010).

Haack provided examples of “marginal” science and witnesses who disturb her for biases and prejudices she perceives in these witnesses. Haack focuses upon Dr. Robert Brent, a toxicologist, who appears to her as Merrell Dow’s expert witness “always ready to testify that Bendectin does not cause birth defects.” Id. At 17. Haack presented no evidence or basis to suggest that Brent was wrong, and indeed, Brent published widely on his views of the subject. Multiple publications do not necessarily mean that Brent was right, but at least he was willing to subject himself to professional peer review, and post-publication, professional challenges. Still, Haack is distressed that Dr Robert Brent opines with “unwarranted certainty” that Bendectin does not cause birth defects, but she offers no suggestion or support that his certainty was or is misplaced.

In stark contrast, Haack expressed no discomfort with Bendectin plaintiffs’ expert witness, Dr Done, or with the facile ease with which he opined with scientific certainty that Bendectin causes birth defects. Here there really is a great deal of empirical evidence, and along with the FDA’s recent approval of Diclegis for use in pregnant women, the evidence has vindicated Dr. Brent’s views on the safety and efficacy of Bendectin/Diclegis. Dr. Done’s subjective appreciation of “flaws” in some clinical studies does not turn criticism into affirmative evidence in favor of the opinion that he so zealously, and overzealously, advocated in many Bendectin cases, for his own substantial pecuniary benefit. What is remarkable about Haack’s article is that she singles out Dr. Brent in the context of a discussion of “marginal” and “willing” testifying scientists, but she omits any mention of the plaintiffs’ cadre of ready, willing, and somewhat disreputable testifiers. Perhaps even more remarkable is that Haack overlooks that Dr. Done was essentially fired from his university for his entrepreneurial testimonial activities of dubious scientific worth, and that he probably lied about his credentials. See Michael Green, Bendectin and Birth Defects: The Challenges of Mass Toxic Substances Litigation 280 – 82 (Philadelphia 1996) (citing decisional law in which Done’s lack of veracity was judicially noted).

Of course, what is most remarkable about Haack’s infatuation with Dr. Alan Done and his mosaic theory is that the theory was the concoction of plaintiffs’ lawyer, Barry Nace, and that the theory leads to such a palpably incorrect result. Barry Nace was one of the lead plaintiffs’ counsel in the Bendectin litigation. Nace was also formerly President of the litigation industry’s principal lobbying organization, the American Trial Lawyers Association (now the AAJ). After the second Ninth Circuit Daubert decision, Nace declined to pursue one of his Bendectin cases, and his client sued him. Nace’s attorney moved for summary judgment in August 1998, on grounds that included the assertion that “courts soundly and uniformly reject the notion that Bendectin causes birth defects.” See David Bernstein, “A Day Late and a Dollar Short on Bendectin” (June 28, 2005).

This is the same Barry Nace lauded by Michael Green for having devised the notorious matrix theory of scientific evidence (a.k.a. the tsumish theory). Michael D. Green, “Pessimism About Milward,” 3 Wake Forest J. Law & Policy41, 62-63 (2013). Professor Haack sees Nace’s matix theory as the practical application of some of her theories. Susan Haack, “Irreconcilable Differences? The Troubled Marriage of Science and Law,” 72 Law & Contemporary Problems 1, 17 (2009); Susan Haack, “Proving Causation: The Holism of Warrant and the Atomism of Daubertm” 4 J. Health & Biomedical Law 273, 274-78 (2008). Haack’s embrace of the dubious Bendectin causal claims as supported by her matrix theory of causal inference raises the issue why we should credit a theory in the face of such a compelling counter example? As Professor Ronald Allen put the matter, before Bendectin was reintroduced into the United States market this year:

“Given the weight of evidence in favor of Bendectin’s safety, it seems peculiar to argue for mosaic evidence from a case in which it would have plainly been misleading.”

Ronald J. Allen and Esfand Nafisi, “Daubert and its Discontents,” 76 Brooklyn L. Rev. 132, 148 (2010). Peculiar indeed. Professor Allen’s point is important for its wide-ranging implications. Methodologies that yield false-positive results are unreliable. Perhaps a methodology can be saved if we could quantify that a given methodology rarely yields such false results, but the matrix theory of Barry Nace and his expert witnesses seems so vague and insubstantial that no one, in all likelihood, could frame a test for the generalized approach. Expert witnesses perhaps should be judged by their track record over time, as well. See David Kaye, “The Experts in Daubert.”[1]

 


[1] Dr. Alan Done (pediatrician, pharmacology, toxicology); Dr. Jay Glasser (biostatistician, epidemiologist); Dr. Adrian Gross (veterinarian); Dr. Stuart Newman (developmental biologist); Dr. Wayne Snodgrass (Assoc. Professor of Pediatrics, Pharmacology, and Toxicology); Dr. Shanna Swan (epidemiologist); Dr. Johannes Thiersch (pathologist and pharmacologist); Dr. John Palmer (Professor of pharmacology).

 

Christopher Bryson and the Problem of Political Science

October 12th, 2013

Fluoridation of water has long been a “political science” issue, with radical libertarians and anarchists viewing fluoridation as the high-water mark of state paternalism.  The motive to misstate and misrepresent the science may at times be obvious, but individual statements, standing alone, may be difficult to judge.

Fluorine chemistry and toxicology are sufficiently advanced that misrepresentations should be easy to detect.  Fluorine is a halogen; the lightest in the series.  As a gas, fluorine is extremely reactive and toxic, as are other halogen gases, such as chlorine.  Fluorine gas was used for uranium enrichment in the Manhattan project, and project scientists conducted research on fluorine toxicity to help them set exposure limits in a new manufacturing process.

As devotees of Breaking Bad no doubt have learned, hydrogen fluoride is extremely toxic and corrosive.  Other halogen-based acids are, of course, toxic and corrosive, such as hydrogen chloride.

Compounds of fluorine are generically fluorides, and the properties of the salts and compounds varies considerably with the cation and the chemical structures involved.  Many modern medications, such as atorvastatin and fluoxetine contain fluorine in their chemical structures.  The toxicology of the fluorine compounds must, therefore, take into account the variability of structure and function of fluorine.  Toxicity of fluorine gas or of hydrogen fluoride cannot be “extrapolated” to a simple sodium salt, and more than the toxicity of chlorine gas can be imply the toxicity or ordinary table salt, sodium chloride.  The allergenicity of a compound such as potassium aluminumtetrafluoride cannot be the basis for asserting the immunogenicity of a simple alkali salt.

Recently, I came across a YouTube video of a journalist, Christopher Bryson, holding forth on his perception of a vast conspiracy to poison people by the fluoridation of drinking water.  Bryson’s passion and selectivity in making his case resembles the deep flaws of our tort system, which allows lawyers and expert witnesses to overwhelm judges and juries with emotion, selectivity, and overstatement.  Bryson refers to all fluorine chemicals, whether the elemental gas, the acid, or the many complex and variable salts as “fluoride.”  Occupational and environmental exposures to hydrogen fluoride are equated with micromolar levels of sodium fluoride in drinking water. Never once does he actually quantitate the exposures he labels as “toxic.” Largely, Bryson proceeds by ad hominems, ad nauseam.  If scientists have industry connections, they are bad, and their science is corrupt.  If a scientist has ever done something productive (e.g., George L. Waldbott), and he opines that water fluoridation is bad, then that scientist must be correct.  Apparently, Bryson has never heard of Linus Pauling and his Vitamin C fiasco.  See K. Frank Austen, M. Dworetzky, Richard S. Farr, G.B. Logan, S. Malkiel, E. Middleton Jr., M.M. Miller, Roy Patterson, C.E. Reed, S.C. Siegel, and P.P. Van Arsdel Jr., “A statement on the question of allergy to fluoride as used in the fluoridation of community water supplies,” 47 J. Allergy & Clinical Immunology 347 (1971) (“no”).

Bryson makes for an interesting case study in hysteria.  He is also very much a public example of the tone and substance of many of the plaintiffs’ theories that clog the civil dockets of our court system.  Bryson’s passion and intensity — heat without illumination  — are reminiscent of the courtroom antics in many a so-called “toxic tort” case.  Bryson’s video is thus a good place to start to try to understand science in the courtroom, and the need for strong gatekeeping.  The potential for inflammatory advocacy, distortion, and misrepresentation have always been part of legal proceedings, but when it comes to advocacy about claims that turn on “scientific” evidence, there is a difference.  Juries in common law cases, in 1789, were not confronted with the abuses of the sort that Bryson so well exemplifies.

The Bryson video led me to look at Bryson’s book, The Fluoride Deception.  The book starts with “Notes on Terminology,” which warns that

“THE TERMS fluorine and fluoride should not be confused in a book about chemical toxicity.”

* * *

“In these pages I’ve tried to be clear when I’m referring to the element fluorine or to a compound, a fluoride. And because different fluoride compounds often have unique toxicities, where relevant or possible, I have also given the compound’s specific name.”

So far so good, but then Bryson, having baited, switches:

“Mostly, however, for simplicity’s sake, I have followed convention and used the shorthand fluoride when referring to the element and its multiple manifestations, a procedure approved and used by the U.S. National Academy of Sciences.”

Christopher Bryson, The Fluoride Deception at xi (2004).

Fluoride deception indeed Mr. Bryson.  The cited source for the indiscriminate use of fluoride makes clear that it uses “fluoride” as a general term when differentiation is not necessary for its discussion.  It is not, however, a basis for conflating or confusing the toxicities of fluorine species or doses.  National Research Council, Biological Effects of Atmospheric Pollutants: Fluorides 3 (1971).  Bryson provides an apt example of how science communication works in politicized contexts, such as the courtroom or the legislature.

LNT in Milward v. Acuity Specialty Products Group

September 28th, 2013

Professor Edward J. Calabrese previously has written about the shadowy origins of the linear no threshold (LNT) model of cancer causation.  See The Dubious Origins of the Linear No Threshold Model of Carcinogenesis (Jan. 10, 2013).  Recently, Calabrese has deepened his historical scholarship with two additional, interesting articles. SeeToxicologist Says NAS Panel ‘Misled the World’ When Adopting Radiation Exposure Guidelines” (Aug. 13, 2013).

These articles, now available online, are important tools in the work chest of lawyers who litigate health effect claims.  Edward J. Calabrese, “How the US National Academy of Sciences misled the world community on cancer risk assessment: new findings challenge historical foundations of the linear dose response,” 87 Arch. Toxicol. (2013) (in press); Edward J. Calabrese, “Origin of the linearity no threshold (LNT) dose–response concept,” 87 Arch. Toxicol. 1621 (2013). Professor Calabrese illuminates the exaggerations and ipse dixit in the origins of the linear-no threshold model, first applied to radiogenic cancers, and later to human carcinogenesis more generally.

On remand from the First Circuit, the trial judge in Milward, now the Hon. Douglas Woodlock, faced a renewed Rule 702 motion directed to Milward’s specific causation expert witnesses.  Milward v. Acuity Specialty Products Group, Inc., Civil Action No. 07–11944–DPW, 2013 WL 4812425 (D. Mass. Sept. 6, 2013). Plaintiffs attempted to invoke the dubious LNT concept to argue that benzene should be in the “differential” for ascertaining the specific cause of Mr. Milward’s APL. In performing a careful Rule 702 analysis, Judge Woodlock rule that, “[t]o the extent Butler [Milward’s expert witness] seeks to establish specific causation based on the argument that any level of benzene is sufficient to cause leukemia—a so-called “no safe level,” “no threshold,” or “linear” model—her opinion is inadmissibly unreliable.”  Id. at *8.

In recognizing Dr. Butler’s reliance upon LNT concepts in civil litigation as unreliable, Judge Woodlock followed the lead of other courts, within the First Circuit, which have previously rejected expert witness opinion testimony founded upon the LNT model.  See, e.g., Whiting v. Boston Edison Co., 891 F.Supp. 12, 25 (D.Mass.1995) (“[t]he linear non-threshold model cannot be falsified, nor can it be validated. To the extent that it has been subjected to peer review and publication, it has been rejected by the overwhelming majority of the  scientific community. It has no known or potential rate of error. It is merely an hypothesis.” ); Sutera v. Perrier Group of America Inc., 986 F.Supp. 655, 666 (D.Mass.1997) (“Accordingly, although there is evidence that one camp of scientists … believes that a non-linear model is appropriate basis for predicting the risks of low-level exposures to benzene, there is no scientific evidence that the linear no-safe threshold analysis is an acceptable scientific technique used by experts in determining causation in an individual instance.”).  Strong precedent outside the First Circuit also supports Judge Woodlock’s holding.  See Allen v. Pennsylvania Eng’g Corp., 102 F.3d 194, 198 (5th Cir.1996); Henricksen v. ConocoPhillips Co., 605 F.Supp. 2d 1142, 1166 (E.D.Wash.2009) (“[Plaintiffs’ expert witness’s] theory that any amount of exposure more than negligible should be considered substantial risk factor for AML flies in the face of the scientific literature reviewed and other expert testimony in this case that there is a threshold or dose below which you do not see a statistically significant risk of developing AML.”); In re W.R. Grace & Co. 355 B.R. 462, 476 (Bankr. D. Del. 2006) (the “no threshold model . . . flies in the face of the toxicological law of dose-response . . . doesn’t satisfy Daubert, and doesn’t stand up to scientific scrutiny”); Cano v. Everest Minerals Corp., 362 F. Supp. 2d 814, 853–54 (W.D. Tex. 2005) (even accepting the linear, no-threshold model for uranium mining and cancer, it is not enough to show exposure, you must show causation as well). See also McClain v. Metabolife Int’l, Inc., 401 F.3d 1233, 1244 (11th Cir. 2005) (“in evaluating the reliability of the experts’ opinions on general causation, it would help to know how much additional risk for heart attack or ischemic stroke Metabolife consumers have over the risks the general population faces”). National Bank of Commerce v. Assoc. Milk Producers, 22 F. Supp. 2d 942, 960 (E.D. Ark. 1998), aff’d, 191 F.3d 858 (8th Cir.1999). See generally Federal Judicial Center, Reference Manual on Scientific Evidence, at 643 n. 28 (3d ed.2011).

The district court in Milward held that because Dr. Butler “did not and could not quantify a threshold exposure level for benzene, Milward cannot posit that his cumulative exposure level crossed a relevant threshold.” Milward, 2013 WL 4812425, at 8.  In addressing Milward’s reliance upon LNT, Judge Woodlock rejected three specious arguments, which frequently recur in Rule 702 litigation.

First, the district saw through the argument that the claimed benzene-APL LNT model was good science because the United States Environmental Protection Agency (EPA) relies upon it.  The EPA applies the LNT model for benzene

“due to uncertainty about the shape of the dose-response curve below 40 ppm-years.”

Id. at 8[1]. The district court recognized that the EPA’s reasoning was a “classic example of a cautious prophylactic administrative rule” that “does not support the reliability of the linear, no-threshold model in establishing specific causation.”  Id.  In so ruling, the Milward district court joins a long line of courts that have distinguished administrative rulemaking from civil litigation standards for causation.  See, e.g., Allen v. Pa. Eng’g Corp., 102 F.3d 194, 198 (5th Cir. 1996)(“This methodology results from the preventive perspective that the agencies adopt in order to reduce public exposure to harmful substances. The agencies’ threshold of proof is reasonably lower than that appropriate in tort law, which traditionally makes more particularized inquiries into cause and effect.”)

Second, the Milward district court also saw through plaintiffs’ argument that the First Circuit’s embrace of its “weight of the evidence” general causation approach, which appears to enjoy support among federal bureaucrats, required approval of plaintiffs’ attempt to use a LNT prophylactic or precautionary approach. Milward, 649 F.3d at 18 & n. 9.  Plaintiffs have the burden of showing reliability of the LNT model, and the EPA’s acknowledged uncertainty about the model for benzene was an insuperable barrier to their success.  Milward, 2013 WL 4812425, at 8 & n.4.

Third, the district court rejected Dr. Butler’s attempt to “bait and switch,” by pointing to a study on hematotoxicity as opposed to carcinogenicity.  Butler argued that there was “no clear evidence of a threshold below which benzene does not cause hematotoxicity in humans.”[2] The court recognized that the study referred to the lack of a hematotoxicity threshold for low average doses of benzene. Hematotoxicity is not necessarily induction of APL; nor was the lack of clear evidence for a threshold evidence against a threshold.

Even in the regulatory realm, the LNT model is losing traction.  See Chlorine Chemistry Council v. EPA, 206 F.3d 1286, 1287 (D.C. Cir. 2000) (invalidating EPA regulation under the Safe Drinking Water Act, when the EPA persisted in using an LNT model, after it had concluded that chloroform, a contaminant in drinking water from chlorination exerted a “a nonlinear mode of carcinogenic action”).  In the scientific realm, researchers can merely watch in amazement at the “political science” that proceeds under a mistaken, outdated model of carcinogenesis.  See, e.g., Brant A. Ulsh, “Checking the Foundation: Recent Radiobiology and the Linear No-Threshold Theory,” 99 Health Physics 747 (2010) (“However, a large and rapidly growing body of radiobiological evidence indicates that cell and tissue level responses to this damage, particularly at low doses and/or dose-rates, are nonlinear and may exhibit thresholds. To the extent that responses observed at lower levels of biological organization in vitro are predictive of carcinogenesis observed in vivo, this evidence directly contradicts the assumptions upon which the microdosimetric argument is based.”); Bernard L. Cohen, “The Linear No-Threshold Theory of Radiation Carcinogenesis Should Be Rejected,” 13 J. Am. Physicians & Surgeons 70, 75 (2008) (“The conclusion from the evidence reviewed in this paper and more extensively elsewhere is that the linear-no threshold theory (LNT) fails very badly in the low-dose region, grossly overestimating the risk from low-level radiation. This means that the cancer risk from the vast majority of normally encountered radiation exposures is much lower than given by usual estimates, and may well be zero or even negative.”); Maurice Tubiana, Ludwig E. Feinendegen, Chichuan Yang, and Joseph M. Kaminski, “The Linear No-Threshold Relationship Is Inconsistent with Radiation Biologic and Experimental Data,” 251 Radiology 13, 13, 15-16, 18 (2009) (noting that LNT model is obsolete in view of known upregulation of cellular protective mechanisms against cancer; “LNT was a useful model half a century ago. But current radiation protection concepts should be based on facts and on concepts consistent with current scientific results and not on opinions. Preconceived concepts impede progress; in the case of the LNT model, they have resulted in substantial medical, economic, and other societal harm.”).



[1] The court EPA Office of Research and Development, Carcinogenic Effects of Benzene: An Update, at 38–39 (April 1998).

[2] Dr. Butler cited Richard B. Hayes, et al., “Benzene and Lymphohemaptopoietic Malignancies in Humans,” 40 Am. J. Indus. Med. 117, 120 (2001).

Differential Diagnosis in Milward v. Acuity Specialty Products Group

September 26th, 2013

Graffiti on the bathroom wall in the building that housed my undergraduate college’s philosophy department:

How does a philosopher treat constipation?

By using iterative disjunctive syllogism.

The joke is that this variety of syllogism is nothing other than reasoning by the process of elimination.

A or B or C

~A

B or C

~B

∴C

The syllogism works as a valid form of argument if the premises are all true.  So, if we start with three possible causes, A, B, and C, and we know that one or more of them caused an outcome, then we might proceed by the process of elimination to show that we can rule out all the others but the alleged cause.  The first line of the syllogism is true if at least one of the disjuncts is true.  As we rule out particular disjuncts upon learning that they are in fact false, we are left we a smaller set of disjuncts.  If we can proceed until we are left with the disjunct of interest, we may actually have succeeded in identifying a cause in fact of the particular case.

In the syllogistic argument above, we must be able to show that A and B are false before we can then conclude that C is true.

In differential etiology, we start with known causes, exposures or conditions that are known to be capable of causing a disease or disorder.  We do not know whether the potential causes were actually in play in a given case.  If we can use this syllogistic reasoning to conclude that the defendant’s product was a cause of the of the plaintiff’s harm, we might actually have shown specific causation in a reliable fashion.  If, however, we cannot proceed to a conclusion that unequivocally includes the defendant’s product, we are left with an indeterminate outcome, and the plaintiff must take nothing.

The Milward case was recently back in the news.  On remand from the First Circuit, the district judge, now the Hon. Douglas Woodlock, faced a renewed Rule 702 motion directed to Milward’s specific causation expert witnesses.  Milward v. Acuity Specialty Products Group, Inc., Civil Action No. 07–11944–DPW, 2013 WL 4812425 (D. Mass. Sept. 6, 2013).

Judge Woodlock wryly commented upon the First Circuit’s ignoring the statutory mandate of Rule 702, by its embracing caselaw that predated the 2000 statutory amendment of the Rule:

“While a 2000 amendment to Fed.R.Evid. 702 codified a rigorous reliability test, the Daubert line of cases has been read by the First Circuit as “demand[ing] only that the proponent of the evidence show that the expert’s conclusion has been arrived at in a scientifically sound and methodologically reliable fashion.” Ruiz–Troche v. Pepsi Cola of Puerto Rico Bottling Co., 161 F.3d 77, 85 (1st Cir.1998). “So long as an expert’s scientific testimony rests upon good grounds based on what is known, it should be tested by the adversarial process, rather than excluded for fear that jurors will not be able to handle the scientific complexities.” Milward, 639 F.3d at 15 (internal quotation and citation omitted).”

Milward, at *3.  After noting the statute’s “rigorous reliability test,” and the First Circuit’s having  diluted the statutory standard by drawing from pre-statute caselaw, Judge Woodlock got down to the business of gatekeeping, by examining the facts of record before him.

The defense’s first challenge was to Milward’s industrial hygienist’s opinion that quantified his benzene exposure.  The industrial hygienist, James Stewart, estimated Milward’s benzene exposure, both total and from individual products.  The defense challenge was interesting, given that plaintiffs have challenged defendants’ use of similar exposure recreations to advance apportionments that will defeat joint and several liability.  The district court denied the defense challenge, and turned its attention to the specific causation issue, which proved to be a good example of patho-epistemology .

The plaintiffs relied upon Dr. Sheila Butler, who was board certified in occupational medicine, pathology, and hematology, to opine that Brian Milward’s exposure was responsible for causing his Acute Promyelocytic Leukemia (“APL”), a rare subtype of Acute Myeloid Leukemia (“AML”). Butler’s opinion was simple if not simpistic:

“there is a ‘reasonable medical probability that there is a direct causal association between Mr. Milward’s APL and his excessive occupational exposure to benzene containing substances’ based primarily on

(1) the fact that his exposure to benzene preceded his development of APL, and

(2) a survey of studies showing increased AML risk following low average dose exposures to benzene.”

Milward at *6.

Simplistic and simply wrong. Butler had equated exposure and some risk, unquantified, with specific causation, an empty and unsupported assertion.  Judge Woodlock did not dignify this subjective opinion with further discussion, but turned his attention to Butler’s “differential diagnosis” analysis by which Butler claimed to have eliminated other potential causes of Milward’s APL such that she could say that benzene was a specific cause.

The district court started from the premise that so-called differential diagnosis is useful and accepted for assessing causation. Id. at *7 (citing Baker v. Dalkon Shield Claimants Trust, 156 F.3d 248, 253 (1st Cir.1998).  For some reason, however, the court emphasized that the differential etiology was particularly appropriate when the expert witness’s opinion lacks a foundation of epidemiologic studies or a “well-established threshold exposure levels at which disease occurs.”  The district court did not explain what it possibly could have meant by this emphasis, and I doubt that there is any basis for the court’s statement.

The real issue in Milward, on remand, was whether Dr. Butler applied the differential etiology in a reliable manner.  The defense argued that Dr. Butler failed to rule out competing risk factors, Milward’s prior smoking, and his morbid obesity, as causes of Milward’s APL.  The court dismissed this challenge with the recognition that plaintiffs might still prevail if Milward’s disease resulted from either benzene and smoking or benzene, smoking, and obesity. Sadly, the court did not address the quality or quantity of the evidence for smoking, or for obesity, and APL; nor did it address the magnitude of the associations that were being claimed by the defense, or by the plaintiffs.  The court did not explore the evidentiary base for the defense assertion that smoking or obesity causes APL such that it should be in the first line of the iterative disjunctive syllogism.

The problem, of course, was not the plaintiffs’ failure to rule out obesity or smoking, but their failure to rule out the unknown factors, which account for the solid majority of APL cases.  Indeed, in the first round of Rule 702 briefings and hearings, plaintiffs’ expert witness, Dr. Martin Smith, opined that between 70 and 80 percent of APL cases are idiopathic; that is, they have no known cause.  Id. at *7.  The syllogism thus becomes very difficult because one proposition in the first line of the argument is that the cause is unknown, and the plaintiff cannot arrive at the conclusion that his APL was caused by benzene unless and until he provides reliable evidence that more likely than not, his APL disease was not caused by one or more of the unknown causes.  In other words, plaintiffs must show that the APL was not a background case that would have occurred regardless of occupational benzene exposure, and perhaps regardless of occupational exposure with obesity and smoking.  Judge Woodlock, relying heavily upon the Restatement (Third) of Torts expressed the matter this way:

“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(4) (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. Id. (‘When the causes of a disease are largely unknown … differential etiology is of little assistance’.).”

In the face of this irrefutable logic of this part of comment c, Butler argued that she had “ruled out” idiopathic APL by “ruling in” benzene.  Of course, benzene had to be postulated as a general cause in order for it to be placed into the first line of the syllogism, but Butler’s assertion about ruling in benzene as a specific cause is truly an ipse dixit, a non sequitur, and a petitio principii, all rolled into one opinion.  After all, the APL case may have arisen out of benzene exposure and the unknown causes, or only the unknown (idiopathic) causes.  Butler cannot rule in benzene until she rules out idiopathic causes as the sole specific causes in this case. To be fair, the prevalence of idiopathic cases cited by Martyn Smith might be lower in a population with heavy benzene exposure, assuming Smith’s general causation were true, but again, such an acknowledgment would only raise the question of what the prevalence of idiopathic cases is in a population of exposure that looked like Mr. Milward’s.

Dr. Butler argued that Martyn Smith had previously ruled in benzene, but that was only as a general cause that can then be represented as one disjunct in the first line of the syllogism.  Here Judge Woodlock identified another gap between Smith’s general causation opinion and Dr. Butler’s attempt to use Smith’s opinion to place benzene into the differential etiology for Mr. Milward.  On this remand, the plaintiffs had to show that “the levels of exposure that are hazardous to human beings generally as well as the plaintiff’s actual level of exposure.” Id. (citing Westberry v. Gislaved Gummi AB, 178 F.3d 257, 263-64 (4th Cir.1999) (talcum powder undisputedly could cause sinus problems, and plaintiff was exposed at levels known to be causative).  The court suggested that Milward had not yet shown that exposure at the levels he experienced could cause APL.  Of course, even if Milward sustained cumulative exposures capable of causing APL, this fact sufficed only to place benzene into the differential diagnosis, and it did not advance the iterative disjunctive syllogism to a conclusion of either a single or multiple disjuncts that included benzene.

Judge Woodlock did a good job of saving the First Circuit from the notoriety of its general causation decision in the Milward case. The new trial court decision is a strong reminder that risk does not equal causation.  Differential etiology cannot rule out idiopathic cause(s) as the sole specific cause of a plaintiff’s disease unless there is a fingerprint of causation that makes the risk identifiable as a cause in a specific case.  Such a fingerprint or biomarker was apparently absent in the Milward case.  Similarly, the differential etiology might rule out putative specific causes on a probabilistic basis if the idiopathic cases made up a small number of all the cases in relation to the number of cases that arise from the exposure that is the subject of the litigation.

The Milward decision joins other soundly decided differential diagnosis cases coming out of the First Circuit.  See, e.g., Plourde v. Gladstone, 190 F. Supp. 2d 708, 722-723 (D. Vt. 2002) (excluding testimony where expert failed to rule out causes of plaintiff’s illness other than exposure to herbicides); Whiting v. Boston Edison Co., 891 F. Supp. 12, 21 n.41 (D. Mass. 1995) (noting that differential diagnosis cannot be used to support conclusion of specific causation when 90% disease cases are idiopathic).

But lest anyone get too comfortable with the notion that this issue has been mastered by the federal judiciary, keep in mind that there are some really poorly reasoned cases out there. See, e.g., Allen v. Martin Surfacing, 263 F.R.D. 47, 56 (D. Mass. 2008) (admitting general and specific causation testimony to be tested by adversary process, rather than excluded altogether, despite paucity of epidemiologic evidence and general acceptance that there are no known causes of amyotrophic lateral sclerosis).

The limits of the “process of elimination” approach has been addressed by some scientific organizations, such as the Teratology Society, in the particularly demanding context of determining a cause for a child’s congenital malformation:

“Biologic plausibility includes a consideration of alternative explanations for the outcome in an individual plaintiff. For example, if a plaintiff has a birth defect syndrome caused by a known genetic disorder, chemical exposure becomes implausible as a cause of the abnormality in that particular individual. The consideration of alternative explanations is sometimes misused by expert witnesses to mean that failure to find an alternative explanation for an outcome is proof that the exposure at issue must have caused the outcome. A conclusion that an exposure caused an outcome is, however, based on positive evidence rather than on lack of an alternative explanation.”

The Public Affairs Committee of the Teratology Society, “Teratology Society Public Affairs Committee Position Paper Causation in Teratology-Related Litigation,” 73 Birth Defects Research (Part A) 421, 423 (2005).

A brief, partial survey of differential etiology cases is set out below.


SECOND CIRCUIT

McCullock v. H.B. Fuller Co., 61 F.3d 1038, 1044 (2d Cir. 1995) (defining differential etiology as an analysis “which requires listing possible causes, then eliminating all causes but one”)

Prohaska v. Sofamor, S.N.C., 138 F. Supp. 2d 422, 439 (W.D.N.Y. 2001) (excluding expert’s opinion and granting summary judgment where expert “was unable to rule out, to a reasonable degree of medical certainty, [plaintiff’s] pre-existing condition, scoliosis, as a current cause of her pain”)

Zwillinger v. Garfield Slope Hous. Corp., 1998 WL 623589, at *20 (E.D.N.Y. Aug. 17, 1998) (excluding testimony and granting summary judgment where expert failed to rule out alternative causes of plaintiff’s immunotoxicity syndrome)

THIRD CIRCUIT

Magistrini v. One Hour Martinizing Dry Cleaning, 180 F. Supp. 2d 584, 608-610 (D.N.J. 2002) (excluding testimony of expert who sought to testify that dry cleaning fluid caused leukemia, but failed to rule out smoking as an alternative cause), aff’d, 68 F. App’x 356 (3d Cir. 2003)

In re Paoli R.R. Yard PCB Litig., 2000 WL 274262, at *5 (E.D. Pa. March 1, 2000) (expert’s opinion should be excluded “because she failed to rule out alternative causes” of plaintiff’s injuries)

Kent v. Howell Elec. Motors, 1999 WL 517106, at * 5 (E.D. Pa. July 20, 1999) (excluding expert testimony and granting summary judgment because expert could “not rule out reasonable alternative theories of what caused the retaining ring to fail”);

O’Brien v. Sofamor, 1999 WL 239414, at *5 (E.D. Pa. Mar. 30, 1999) (excluding expert’s testimony and granting summary judgment where plaintiff “offer[ed] no evidence that [plaintiff’s experts] performed a differential diagnosis, or even considered other potential causes” of plaintiff’s back condition)

Schmerling v. Danek Med., Inc., 1999 WL 712591, at *9 (E.D. Pa. Sept. 10, 1999) (excluding expert’s testimony and granting summary judgment on the grounds that expert’s failure to rule out alternative causes “alone warrants a determination that the expert’s methodology is unreliable”);

Turbe v. Lynch Trucking Inc., 1999 WL 1087026, at *6 (D.V.I. Oct. 7, 1999) (excluding expert’s testimony where expert “expressed awareness of obvious alternative causes” yet “did not investigate any other possible causes”);

Reiff v. Convergent Technologies, 957 F. Supp. 573, 582-83 (D.N. J. 1997) (excluding expert’s testimony and granting summary judgment where expert failed to rule out alternative causes of plaintiff’s carpal tunnel syndrome)

Rutigliano v. Valley Bus. Forms, 929 F. Supp. 779, 787 (D.N.J. 1996) (excluding expert’s testimony and granting summary judgment where the “record is replete with evidence, including [the expert’s] own admissions, that [plaintiff’s] symptoms could be attributable to medical conditions other than formaldehyde sensitization”)

Diaz v. Matthey, Inc., 893 F. Supp. 358, 376-377 (D.N.J. 1995) (excluding testimony and granting summary judgment where expert failed to rule out alternative causes for plaintiff’s asthma) (Irenas, J.)

Wade-Greaux v. Whitehall Labs., Inc., 874 F. Supp. 1441 (D.V. I.), aff’d, 46 F.3d 1120 (3d Cir. 1994) (excluding testimony of expert who failed to rule out alternative causes of plaintiff’s birth defects)

FOURTH CIRCUIT

Westberry v. Gislaved Gummi AB, 178 F.3d 257, 262-263 (4th Cir. 1999) (“Differential diagnosis, or differential etiology, is a standard scientific technique of identifying the cause of a medical problem by eliminating the likely causes until the most probable one is isolated”)

Shreve v. Sears, Robuck & Co., 166 F. Supp. 2d 378, 397-98 (D. Md. 2001) (excluding testimony where expert failed to rule out other causes of plaintiff’s injury other than an alleged defect in snow thrower)

Fitzerald v. Smith & Nephew Richards, Inc., 1999 WL 1489199 (D. Md. Dec. 30, 1999) (excluding expert’s testimony and granting summary judgment where expert “failed to rule out what could have been another cause of [plaintiff’s] condition”)

Aldridge v. Goodyear Tire & Rubber Co., 34 F. Supp. 2d 1010, 1024 (D. Md. 1999), vacated on other grounds, 223 F.3d 263 (4th Cir. 2000) (excluding testimony of plaintiffs’ experts where they “failed to adequately address possible alternative causes of plaintiffs’ illnesses”)

Oglesby v. General Motors Corp., 190 F.3d 244, 250 (4th Cir. 1999) (affirming exclusion of testimony where “as a matter of logic, [the expert witness] could not eliminate other equally plausible causes” of cracked plastic inlet);

Driggers v. Sofamor, S.N.C., 44 F. Supp. 2d 760, 765 (M.D.N.C. 1998) (excluding expert’s testimony and granting summary judgment where “expert failed to rule out other possible causes of [plaintiff’s back] pain”);

Higgins v. Diversey Corp., 998 F. Supp. 598, 603 (D. Md. 1997), aff’d, 135 F.2d 769 (4th Cir. 1998) (excluding expert’s testimony that the accidental inhalation of a bleach caused plaintiff’s injuries, where expert “admit[ted] that he [could] not rule out several other possible causes”)

FIFTH CIRCUIT

Michaels v. Avitech, Inc., 202 F.3d 746, 753 (5th Cir. 2000) (excluding testimony when “plaintiff’s experts wholly fail[ed] to address and rule out the numerous other potential causes” of an aircraft disaster)

Black v Food Lion, Inc, 171 F3d 308 (5th Cir 1999) (expert witness, purporting to use a differential diagnosis, testified that plaintiff’s slip in the supermarket caused fibromyalgia, which is largely idiopathic) (“This analysis amounts to saying that because [the physician] thought she had eliminated other possible causes of fibromyalgia, even though she does not know the real ‘cause,’ it had to be the fall at Food Lion. This is not an exercise in scientific logic but in the fallacy of post-hoc propter-hoc reasoning, which is as unacceptable in science as in law.”)

Conger v. Danek Med., Inc., 1998 WL 1041331, at *5-6 (N.D. Tex. Dec. 14, 1998) (excluding expert’s testimony and granting summary judgment when expert “had not attempted to rule out [other potential sources] as causes for [plaintiff’s back] pain”);

Leigh v. Danek Med., Inc., 1998 WL 1041329, at *4-5 (N.D. Tex. Dec. 14, 1998) (excluding expert’s testimony and granting summary judgment where expert failed to rule out alternative causes of plaintiff’s back pain)

Bennett v. PRC Public Sector, 931 F. Supp. 484, 492 (S.D. Tex. 1996) (excluding testimony of expert who failed to consider and rule out alternative causes of plaintiff’s repetitive motion disorders)

SIXTH CIRCUIT

Nelson v. Tennessee Gas Pipeline Co., 1998 WL 1297690, at *6 (W.D. Tenn. Aug. 1, 1998) (excluding testimony of expert who “failed to engage in adequate techniques to rule out alternative causes and offers no good explanation as to why his opinion is nevertheless reliable in light of other potential causes of the alleged injuries”);

Downs v. Perstorp Components, 126 F. Supp. 2d 1090, 1127 (E.D. Tenn. 1999) (excluding expert testimony as to whether exposure to chemicals caused plaintiff’s injuries where expert failed to rule out alternative causes)

EIGHTH CIRCUIT

Jisa Farms, Inc. v. Farmland Indus., No. 4:99CV3294, 2001 U.S. Dist. LEXIS 26084 (D. Neb. 2001)

Thurman v. Missouri Gas Energy, 107 F. Supp. 2d 1046, 1058 (W.D. Mo. 2000) (expert’s opinion “that the pipeline failed because of corrosion” was excluded and summary judgment granted where expert reached the conclusion “without eliminating other causes”)

Bruzer v. Danek Med., Inc., 1999 WL 613329, at *8 (D. Minn. Mar. 8, 1999) (excluding expert’s testimony and granting summary judgment where expert did “not attempt to rule out any alternative potential causes for [plaintiff’s] continuing and increasing [back] pain”)

National Bank of Commerce v. Assoc. Milk Producers, 22 F. Supp. 2d 942, 963 (E.D. Ark. 1998), aff’d, 191 F.3d 858 (8th Cir.1999) (excluding testimony and granting summary judgment where expert did “not successfully rule out other possible alternative causes” for cancer)

TENTH CIRCUIT

In re Breast Implant Lit., 11 F. Supp. 2d 1217, 1234 (D. Colo. 1998) (excluding expert testimony where expert failed to “explain what alternative causes he considered, or how he ruled out other possible causes” of plaintiffs’ auto- immune disease)

Stover v. Eagle Products, 1996 WL 172972, at *11 (D. Kan. Mar. 19, 1996) (excluding testimony of expert who “[did] not explain in any meaningful detail how he [was] able to exclude the numerous multiple alternative causes” of injury to plaintiff’s dogs)

ELEVENTH CIRCUIT

Rink v. Cheminova, Inc., 400 F.3d 1286, 1295 (11th Cir. 2005) (“[I]n the context of summary judgment . . . differential diagnosis evidence by itself does not suffice for proof of causation.”)

STATE COURT CASES

Blanchard v. Goodyear Tire & Rubber Co.,  2011 Vt. 85, 30 A.3d 1271 (2011) (holding that plaintiff’s claim that his NHL was caused by benzene was not reliably supported by differential diagnosis when a large percentage of NHL cases have no known cause)

Bradford Hill on Statistical Methods

September 24th, 2013

I am indebted to the article by Dr. Frank Woodside and Allison Davis on the so-called Bradford Hill criteria, for reminding me about the distorted view that some plaintiffs’ counsel advance in litigation about Bradford Hill’s view of statistical testing.  Frank C. Woodside, III & Allison G. Davis, “The Bradford Hill Criteria: The Forgotten Predicate,” 35 Thomas Jefferson L. Rev. 103 (2013).  Dr. David Schwartz has also written an insightful blog post on Bradford Hill.  See David Schwartz, “5 Reasons to Apply the Bradford Hill Criteria in Your Next Case” (Sept. 20, 2013).

Here is where Bradford Hill postulates the position of a research question before his famous nine factors come into the analysis:

“Disregarding then any such problem in semantics we have this situation. Our observations reveal an association between two variables, perfectly clear-cut and beyond what we would care to attribute to the play of chance. What aspects of that association should we especially consider before deciding that the most likely interpretation of it is causation?”

Austin Bradford Hill, “The Environment and Disease: Association or Causation?” 58 Proc. Royal Soc’y Med. 295, 295 (1965).

The starting point, before the Bradford Hill nine factors come into play, requires a “clear-cut” association, which is “beyond what we would care to attribute to the play of chance.”  What is “clear-cut” association?  The most reasonable interpretation of Bradford Hill is that the starting point is an association that is not the result of chance, bias, or confounding.

I parted company with Woodside and Davis over whether Bradford Hill was somehow dismissive of the role of assessing chance in explaining an association.  In acknowledging any validity in the plaintiffs’ interpretation of Bradford Hill’s 1965 paper, Woodside and Davis, do an injustice, in my view, to Bradford Hill’s careful articulation of his position.

The starting position, quoted above, seems very clear, but Woodside and Davis note that later on in his speech, Bradford Hill suggested that tests of significance do not contribute to proof of the hypothesis.  Bradford Hill’s actual words are, however, fairly precise:

“No formal tests of significance can answer those questions. Such tests can, and should, remind us of the effects that the play of chance can create, and they will instruct us in the likely magnitude of those effects. Beyond that they contribute nothing to the ‘proof’ of our hypothesis.”

Bradford Hill at 299.

Plaintiffs’ counsel sometimes argue that this passage means that significance testing contributes “nothing” to proving the hypothesis, but this ignores two key points.  First, the argument ignores where in the text the passage occurs:  after Bradford Hill’s discussion of the nine factors.  Bradford Hill’s statement can be understood only as a reflection back on the nine factors.  The phrase “those questions” refers back to the nine factors, and this is the limitation that Bradford Hill is placing upon “formal tests of significance.” The starting point, before the nine factors are examined, is, after all, a “clear-cut” association, “beyond what we would care to attribute to the play of chance.”

Second, plaintiffs’ counsel’s argument ignores the clear meaning of the “[b]eyond that” phrase.  Beyond what?  Well, the limited role is nothing other than quantifying the play of chance in the observed results.  This role is hugely important, and of course, is incorporated into the starting point before the nine factors are examined.  In modern analyses, the role of random variability would actually be explored in the analysis of the exposure-outcome gradient, and perhaps in some of the other nine factors as well.  Bradford Hill implied that a statistically significant association was a preliminary step, after which the really hard work began.

It would be unfair to Bradford Hill to read into his statement much about “strict” testing versus a more flexible inferential approach in selecting or interpreting a Type I error rate.  By the time he presented his Presidential Address to the Royal Society of Medicine in 1965, much fur had flown in the disputes between Neyman and Fisher.  Resolving Bradford Hill’s view on the dispute is not a pressing issue because on either account, the quantification of the p-value is an extremely important step in evaluating scientific data.

In his textbook on medical statistics, Bradford Hill expands on the role of statistical analysis in medicine:

“Are simple methods of the interpretation of figures only a synonym for common sense or do they involve an art or knowledge which can be imparted? Familiarity with medical statistics leads inevitably to the conclusion that common sense is not enough. Mistakes which when pointed out look extremely foolish are quite frequently made by intelligent persons, and the same mistakes, or types of mistakes, crop up again and again. There is often lacking what has been called a ‘statistical tact, which is rather more than simple good sense’. That tact the majority of persons must acquire (with a minority it is undoubtedly innate) by a study of the basic principles of statistical method.”

Austin Bradford Hill, Principles of Medical Statistics at 2 (4th ed. 1948) (emphasis in original).

Even in this early work though, Bradford Hill acknowledges the limits of statistical methods:

“It is a serious mistake to rely upon the statistical method to eliminate disturbing factors at the completion of the work.  No statistical method can compensate for a badly planned experiment.”

Id. at 4 (emphasis in original).  That statistical method cannot save a poorly planned experiment (or observational study) does not, however, imply that statistical methods are not needed to interpret a properly planned experiment or study.

In the summary section of the first chapter, Bradford Hill removes any doubt about his view of the importance, and the necessity, of statistical methods:

“The statistical method is required in the interpretation of figures which are at the mercy of numerous influences, and its object is to determine whether individual influences can be isolated and their effects measured.”

Id. at 10 (emphasis added).