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Wells v. Ortho Pharmaceutical Corp. Reconsidered – Part 2

November 13th, 2012

How then did Ortho lose a case in which the trial judge, sitting as the trier of fact, declared that overall the studies failed to show that the spermicide caused any or all of Katie Wells’ birth defects?  First, let’s look at the liability case to the extent it depended upon scientific evidence up to the time of actual use of the product by the mother.

State of the Art

The state of the art in 1980 was based in large measure on 30 years of marketing experience.

The plaintiffs’ expert witnesses relied upon a limited number of papers and studies that could have been the basis for a determination that defendant had “knowledge,” actual or constructive, that the product caused birth defects of the type experienced by Katie Wells.

According to the court, the articles cited by some of the plaintiffs’ expert witnesses, in support for a warning on or before November 1980, suggested “the possibility of such a risk” from spermicides.  615 F. Supp. at 294. The studies themselves did not claim that there was a “known” causal relationship between spermicides and any birth defects, let alone the kind of malformations found in Katie Wells. Furthermore, the plaintiffs’ hired expert witnesses did not assert that any of the articles from this time period permitted such a conclusion.

A larger problem loomed in the interpretation of the early studies and papers.  Along with non-ionic surfactants, phenylmercuric acetate (PMA) (and also phenylmercuric nitrate) was used in spermicidal preparations.  There was some concern over the use of mercury compounds, which had known animal teratogenicity.  See FDA OTC Panel on Contraceptive and Other Vaginal Drug Products, Summary minutes of the fourth meeting November 18-19, 1973 (Adopted January 1974).  The Panel noted that a report was presented on phenylmercuric acetate (PMA), as a spermicidal agent and active ingredient of some vaginal contraceptive preparations. The report failed to find evidence of adverse effects on women or on human embryos, but it did note that teratogenic effects had been observed in animal experiments.

1.  R. Belsky, “Vaginal contraceptives–a time for reappraisal?” Population Reports:  Series H – Barrier Methods 37 (Jan. 1975).  This appears to be a review article, and none of the witnesses attributed any data or conclusions emanating from the paper.  The court described this article, as urged by some of plaintiffs’ hired experts to support a basis for warning on the product sold by Ortho and used by Katie Wells’ mother in 1980.  The alleged concern about spermicides is not specified as relating to non-ionic or mercury preparations.

2. Frank W. Oechsli, Studies of the Consequences of Contraceptive Failure (Apr. 8, 1976) (unpublished study).  According to the court, this study was the “Final Report for Contract NO1-HD-5-2816” for the Contraceptive Evaluation Branch, Center for Population Research, National Institute of Child Health and Development.   The court reports that plaintiffs’ expert witnesses cited this unpublished study as a basis for the defendant’s need to warn.

The elephant on the table for the Oechsli manuscript was why it was never published.  The plaintiffs’ expert witnesses sang the praises of NIH investigators, but obviously these investigators never thought that their work was sufficiently important or valid to publish and share with the medical and scientific community.  The lead author of this unpublished study, Frank W. Oechsli, has 17 publications listed in PubMed, none of which address potential associations between congenital malformations and spermicide use.

The availability of the Oechsli unpublished study to Ortho, before 1980, was disputed. Plaintiffs and their witnesses argued that Ortho could have obtained it by way of a FOIA request, and that it was cited in the Harlap article, infra, which was published in March 1980.  One of plaintiffs’ witnesses colorfully described Ortho as “asleep at the wheel” for not having obtained the unpublished paper. 615 F. Supp. at 277.

The defendant offered undisputed factual testimony that the NIH told the FDA Advisory Committee, considering safety and efficacy of non-ionic spermicides, that the study would not be available during the work of the Committee, which concluded in 1978.  615 F. Supp. at 280.  The NIH was aware that the FDA Committee was meeting, but never otherwise offered to share the unpublished Oechsli study.  In 1978, the FDA Committee presented its final report to the FDA.  The Committee report, which classified  non-ionic surfactants as safe, effective, and properly labeled, for use as spermicidal preparations.  Id. at 279.

In any event, Dr. Buehler, one of plaintiffs’ hired experts, described the Oechsli study as raising a “question and possible relationship” between spermicides and birth defects.  Although the defense had raised the problem of confounding with PMA, which was known to be teratogenic in animals, the court never disambiguated the plaintiffs’ broad brush references to “spermicides,” which could have referred to non-ionic compounds, mercury compounds, or both, in Oechsli’s study, as well as other of the early studies.

3.  S. Harlap, P. Shiono, S. Ramcharan, “Spontaneous foetal losses in women using different contraceptives around the time of conception,” 9 Internat’l J. Epidem. 49 (1980). The plaintiffs’ expert witnesses cited the Harlap study only because it referenced the Oechsli study.  Harlap, et al., however, reported that their data were contrary to those of the unpublished Oechsli study:  “Previous reports [citation to Oechsli] of an excess risk associated with spermicides are not borne out by this study.” Id. at 56.

4. E. S. Smith, C.S. Dafoe, J.R. Miller, P. Banister, “An epidemiological study of congenital reduction deformities of the limbs,” 31 Brit. J. Prev. & Social Med. 39 (1977). This study did evaluate limb deformities,  and compared many different maternal exposures among cases and controls, using a chi-squared analysis.  With two control groups combined, the chi-square was marginally significant for contraceptive foam or jelly, but no correction was made for the multiple comparisons. The authors noted that this exposure, foam or jelly, involved some products that were known to be teratogenic in animals (mercury compounds).

5. Warburton, Environmental Influences on Rates of Chromosome Anomalies, American Journal of Human Genetics – ABSTRACT (1980).  One of the plaintiffs’ witnesses relied upon this abstract, which identified spermicides as a possible factor in spontaneous abortions.  Dr. Holbrook suggested that this finding might mean that spermicides were teratogenic as well.  The completed paper, however, failed to confirm the suggestion in the Warburton abstract.  615 F. Supp. at 284.

 

The court found that at the time Katie Wells used Ortho’s product in fall of 1980, Ortho was negligent in failing to warn about an increased risk of birth defects that “might” arise from use of the product. 615 F. Supp. at 294 (emphasis added). Various article and studies suggested “the possibility of such a risk” in this time period. Id. (emphasis added).

The court relied heavily upon plaintiffs’ witnesses’ distorted testimony on this point.  For instance, Dr. Dick Gourley, testifying for the plaintiffs, opined that “as soon as the first study is done and any information that is provided … gives the hint that there is a possibility of a drug causing birth defects,” a labeled warning should be provided. Id. at 276.  Dr. Gourley thus testified that Ortho should have warned about an increased risk of birth defects “soon after that possibility was suggested by the Oechsli study in 1976, and no later than the publication of the Smith study in 1977.” Id.  Judge Shoob found Gourley “undogmatic,” and thus very credible! Dr. Gourley not only offered opinions that did not conform to the legal standard, he offered opinions based upon his own personal, subjective, ethical and emotive feelings. 615 F. Supp. at 277 n.19.  Unlike the treatment of defense experts who possibly strayed outside their fields of expertise, Judge Shoob regarded testimonial frolic and detours, such as Dr. Gourley’s to reflect their emphatic, and confident testimony.  Id.

The court similarly appeared to embrace plaintiffs’ expert witness, Dr. Sutherland, who opined that Ortho’s warnings were inadequate on grounds of the Oechsli unpublished paper (1976), and the Smith (1977) study, which together raised a “serious potential” that “spermicides increase the risk of fetal injury.” 615 F. Supp. at 274.  Remarkably, Judge Shoob did not require the plaintiffs to address, and to present evidence of, the spermicide at issue, or the specific congenital malformation at issue. The plaintiffs’ witnesses’ testimonies, as summarized by Judge Shoob, refer to possibilities, potentials, and hints of broad, ill-defined fetal harms, but this was held sufficient to satisfy plaintiffs’ burden of showing actual or constructive knowledge.  Having conflated hunches with knowledge, the court concluded that:

“This knowledge gave rise to a duty by defendant to warn consumers and certain health professionals of this possible risk.”

Id. at 294.

How did Ortho lose the state of the art issue?  Ortho lost when Judge Shoob allowed:

  • hints and hunches to substitute for knowledge;
  • obscure or unpublished papers to substitute for peer-reviewed, published, data-based, carefully analyzed studies;
  • that the evidence no longer had to relate to Ortho’s product, but could include another product, which contained a mercury compound known to cause birth defects in animals;
  • any fetal harm to substitute for the relevant congenital malformations; and
  • exculpatory opinions, including those of the FDA’s Advisory Committee, to be excluded from consideration.
(to be continued)

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Wells v. Ortho Pharmaceutical Corp. Reconsidered – Part 1

November 12th, 2012

In Matrixx Initiatives, Inc. v. Siracusano, 131 S.Ct. 1309 (2011), the Supreme Court, speaking through Justice Sotomayor, wandered into a discussion whether statistical significance was necessary for a determination of the causality of an association:

“We note that courts frequently permit expert testimony on causation based on evidence other than statistical significance. See, e.g., Best v. Lowe’s Home Centers, Inc., 563 F. 3d 171, 178 (6th Cir 2009); Westberry v. Gislaved Gummi AB, 178 F. 3d 257, 263–264 (4th Cir. 1999) (citing cases); Wells v. Ortho Pharmaceutical Corp., 788 F. 2d 741, 744–745 (11th Cir. 1986). We need not consider whether the expert testimony was properly admitted in those cases, and we do not attempt to define here what constitutes reliable evidence of causation.”

Id. at 1319.

As I have pointed out previously, the Court’s citation to these three cases was jarring for their irrelevance, and for the questionable scholarship involved.

The first two cases cited involved differential etiology  to assess specific causation, not general causation.  As most courts have recognized, this assessment strategy requires that general causation has already been established. See, e.g., Hall v. Baxter Healthcare, 947 F. Supp. 1387 (D. Ore. 1996).  These cases did not, therefore, even touch on the use of statistical significance to establish general causation. There was no statistical analysis in those cases, and nothing to judge significant or insignificant.

The citation to the third case, Wells, is noteworthy because the case has nothing to do with adverse event reports or the lack of statistical significance.  Wells involved a claim of birth defects caused by the use of spermicidal jelly contraceptive, which had been the subject of several studies, one of which at least yielded a statistically significant increase in detected birth defects over what was expected.  Wells v. Ortho Pharmaceutical Corp., 615 F. Supp. 262 (N.D. Ga. 1985), aff’d and rev’d in part on other grounds, 788 F.2d 741 (11th Cir.), cert. denied, 479 U.S.950 (1986).  Wells could thus hardly be an example of a case in which there was a judgment of causation based upon a scientific study that lacked statistical significance in its findings. Of course, finding statistical significance is just the beginning of assessing the causality of an association; Wells was notorious for its poor assessment of all the determinants of scientific causation.

As I pointed out in Matrixx Unloaded, the citation to Wells was remarkable because the Wells decision has been widely criticized for its failure to evaluate the entire evidentiary display, as well as for its failure to rule out bias and confounding in the studies relied upon by the plaintiff.[i]

A few years later, another case in the same judicial district against the same defendant for the same product resulted in the grant of summary judgment.  Smith v. Ortho Pharmaceutical Corp., 770 F. Supp. 1561, 1582 (N.D. Ga. 1991) (supposedly distinguishing Wells on the basis of more recent studies).  Some legal scholars have been content to point out that the science had matured with the passage of time, from the point that there was sufficient evidence to support plaintiffs’ case (in Wells) to the point that the evidence was so overwhelmingly adverse to plaintiffs that summary judgment for the defense was appropriate (in Smith).  While this suggestion has the virtue of simplicity, it fails to look at what really happened in Wells, and to analyze the evidence in front of the Wells court.

Another remarkable aspect of the Supreme Court’s citation to Wells is that the case, and all it stands for, was overruled sub silentio by the Supreme Court’s own decisions in Daubert, Joiner, Kumho Tire, and Weisgram.  And if that did not kill the concept, then there was the simple matter of a supervening statute:  the 2000 amendment of Rule 702, of Federal Rules of Evidence. Citing a case as jurisprudentially dead and discredited as Wells could have been sloppy scholarship and lawyering.  The principle of charity, however, suggests it was purposeful, and that is a frightful prospect.

Katie Wells was conceived sometime in the month of October 1980.  Her mother was using the defendant’s product, Ortho-Gynol Contraceptive Jelly, with its active ingredient, a non-ionic surfactant called p-diisobutylphenoxypolyethoxyethanol or octoxynol-9, from July until mid-November 1980.  Defendant Ortho had manufactured and marketed this product since 1950, without any warning that the product causes birth defects. 615 F. Supp. at 268-69.  Ortho’s defense consisted in denying general and specific causation, and noting that in the fall of 1980, “no published reports or studies had concluded that spermicides cause birth defects,” and that “it had received no other complaints nor had access to any other evidence suggesting a link between its Product and birth defects.” 615 F. Supp. at 269.

Key issues in Wells were whether the state of the art required a warning on product in 1980, when used, and whether, as of the time of the trial in 1984, plaintiffs could establish cause in fact.

The district judge, Judge Marvin Shoob, heard the case as the trier of fact.  Both sides waived their rights to a jury trial in part because of the number of witnesses could not be accommodated within the time scheduled for the trial.  Given that the plaintiffs called so many redundant witnesses, a reasonable observer may suspect that the plaintiffs wanted a bench trial.  Perhaps there was something about the relationship between Katie’s mother and father to give plaintiffs’ counsel pause.  Katie’s father, Mr. Gary Wells, was not a party; only her mother was claiming economic damages.  Perhaps Katie’s father’s admitted substantial use of illegal, recreational drugs, pushed plaintiffs to make this choice.  Katie’s mother admitted to using only therapeutic drugs, Decadron for bronchitis, and Amoxicillin during her pregnancy, but her father admitted to using LSD, amphetamines, methaqualone, and marijuana.  Id. at 269. The defense probably agreed, hoping to avoid an unduly sympathetic jury, and to gain a more analytical decision maker.

Jurisdiction in Wells was based upon diversity of citizenship; the court was bound to apply Georgia law under controlling choice-of-law precedent.  Georgia law requires plaintiffs to prove medical causation “reasonable degree of medical certainty.”  See Parrott v. Chatham County Hospital Authority, 145 Ga.App. 113, 115, 243 S.E.2d 269 (1978); Robertson v. Emory University Hospital, 611 F.2d 604, 608 n. 13 (5th Cir.1980); Watson v. United States, 346 F.2d 52, 54 (5th Cir.1965), cert. denied, 382 U.S. 976 (1966). 615 F. Supp. at 295. Plaintiffs, under Georgia law, must show more than a “bare possibility” of causation, as well as ruling out other theories that are equally plausible. Id. (citing Maddox v. Houston County Hospital Authority, 158 Ga.App. 283, 284, 279 S.E.2d 732 (1981)).

According to Georgia law of negligence, a manufacturer must exercise reasonable care to warn of dangers of which it has “actual or constructive knowledge,” when the product was sold and delivered.  Id. (citations omitted).

In deciding this case, Judge Shoob began defensively, on thin ice, by declaring that he had to make a “legal” decision, not a medical decision. Id. at 266.  This defensive prelude was curious because Georgia law clearly imported “knowledge” into both the duty to warn, and into resolution of the causal issue.  The requisite knowledge could come only from the scientific evidence that the parties tried to marshal.  The defensive prelude was also curious because, as we shall see, Judge Shoob allowed the plaintiffs’ expert witnesses to opine about their subjective perceptions that warnings should be required upon suspicion of harm.

It bears pointing out that, as in Ferebee, Federal Rule of Evidence 702 or 703 is never mentioned in Judge Shoob’s decision. There appears to have been no defense challenges to the qualifications or the “helpfulness” of any of the plaintiffs’ witnesses.  There are no challenges to any expert witness’s qualifications. There are no Frye challenges discussed.

On re-reading Judge Shoob’s opinion, the most salient feature is the absence of any discussion of the “point estimates” of association or “effect size” in any of the studies discussed.  Similarly, Judge Shoob fails to mention the extent of the random error in any study, either in the form of p-values of in confidence intervals.  There is an occasional hint that studies are too small to yield meaningful findings, but no power calculations or assessments are provided, and no alternative hypotheses specified.  There is no consideration of multiple comparisons, which may have diluted the usual interpretation of significance probability. Judge Shoob failed to engage in the scientific studies or the evidence, which was offered to him as the trier of fact.

Notwithstanding the failure to consider important rules of evidence, and the scientific evidence, Judge Shoob appreciated that there was a failure of proof on the part of the plaintiffs:

“Although some of the studies suggested a connection between spermicides and birth defects, overall the studies failed to show conclusively whether or not the spermicide caused any or all of the birth defects suffered by Katie Wells.”

Id. at 266. How then did Ortho loose?

(to be continued).

[i] See, e.g., James L. Mills and Duane Alexander, “Teratogens and ‘Litogens’,” 15 New Engl. J. Med. 1234 (1986); Samuel R. Gross, “Expert Evidence,” 1991 Wis. L. Rev. 1113, 1121-24 (1991) (“Unfortunately, Judge Shoob’s decision is absolutely wrong. There is no scientifically credible evidence that Ortho-Gynol Contraceptive Jelly ever causes birth defects.”). See also Editorial, “Federal Judges v. Science,” N.Y. Times, December 27, 1986, at A22 (unsigned editorial) (“That Judge Shoob and the appellate judges ignored the best scientific evidence is an intellectual embarrassment.”);  David E. Bernstein, “Junk Science in the Courtroom,” Wall St. J. at A 15 (Mar. 24,1993) (pointing to Wells as a prominent example of how the federal judiciary had embarrassed American judicial system with its careless, non-evidence based approach to scientific evidence); Bert Black, Francisco J. Ayala & Carol Saffran-Brinks, “Science and the Law in the Wake of Daubert: A New Search for Scientific Knowledge,” 72 Texas L. Rev. 715, 733-34 (1994) (lawyers and leading scientist noting that the district judge “found that the scientific studies relied upon by the plaintiffs’ expert were inconclusive, but nonetheless held his testimony sufficient to support a plaintiffs’ verdict. *** [T]he court explicitly based its decision on the demeanor, tone, motives, biases, and interests that might have influenced each expert’s opinion. Scientific validity apparently did not matter at all.”) (internal citations omitted); Troyen A. Brennan, “Untangling Causation Issues in Law and Medicine: Hazardous Substance Litigation,” 107 Ann. Intern. Med. 741, 744-45 (1987) (describing the result in Wells as arising from the difficulties created by the Ferebee case; “[t]he Wells case can be characterized as the court embracing the hypothesis when the epidemiologic study fails to show any effect”).  Kenneth R. Foster, David E. Bernstein, and Peter W. Huber, eds., Phantom Risk: Scientific Inference and the Law 28-29, 138-39 (MIT Press 1993) (criticizing Wells decision); Hans Zeisel & David Kaye, Prove It With Figures: Empirical Methods in Law and Litigation § 6.5, at 93(1997) (noting the multiple comparisons in studies of birth defects among women who used spermicides, based upon the many reported categories of birth malformations, and the large potential for even more unreported categories); id. at § 6.5 n.3, at 271 (characterizing Wells as “notorious,” and noting that the case became a “lightning rod for the legal system’s ability to handle expert evidence.”).

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Evidence-Based Specific Causation

November 7th, 2012

In the last post, I discussed an important article by Professors Davidson and Guzelian, on the legal implications of evidence-based medicine (EBM).  Terence M. Davidson & Christopher P. Guzelian, “Evidence-based Medicine (EBM): The (Only) Means for Distinguishing Knowledge of Medical Causation from Expert Opinion in the Courtroom,” 47 Tort Trial & Ins. Practice L. J. 741 (2012) [cited as Davidson].

Their criticism of the deficiencies in current gatekeeping practice cries out for reform of much current judicial practice.  Education of the judiciary in EBM would be helpful to both plaintiffs and defendants in civil cases, as well as prosecutors and defendants in criminal cases.  I will leave for another day a discussion of whether the boundary between knowledge and “mere opinion” is so easily discernible.

Although the authors’ call for EBM in judicial decisions is timely and needed, I noted my dissent to their assessment of one defense expert witness’s specific causation opinion in the hormone therapy litigation. Davidson and Guzelian criticize one district judge for having admitted the challenged testimony of a defense expert witness, Dr. Blaustein, who opined that (1) estrogen + progesterone combination post-menopausal hormone replacement therapy (CHRT) has not been shown to cause breast cancer, and (2) there is no generally accepted method for determining a cause of a woman’s breast cancer.  Cross v. Wyeth Pharms., Inc., CASE NO.: 8:06-cv-429-T-23AEP, 2011 U.S. Dist. LEXIS 89078; 2011 WL 3498305 (M.D. Fla. 2011) (Merryday, J.).

Here is how Davidson & Guzelian put the matter:

“Blaustein also opined that there is no generally accepted method for diagnosing specific medical causation—that is, whether a medical intervention or treatment, even if it is known to generally cause a result ‘X’ (e.g., breast cancer), caused a particular patient’s result ‘X’. Blaustein’s statement, accepted by the judge as befitting of presentation to the jury, is ‘simply false’.”

The claim that Blaustein’s statement is “simply false” is pretty strong for both general and specific causation, and partially explains my initial dissent.  The prestige of the Women’s Health Initiative (WHI), a large, randomized, clinical meta-trial of  CHRT, with its finding of an increased risk for breast cancer among women, certainly has made Dr. Blaustein’s opinion on general causation a distinctly minority view.  There are, however, some careful authors who have challenged the findings of the WHI on grounds of internal and external validity.  See, e.g., Samuel Shapiro, Richard Farmer, Helen Seaman, J. C. Stevenson, “Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies: part 2. The Women’s Health Initiative: estrogen plus progestogen,” 37 J. Family Planning & Reproductive Health Care 165, 165 (2011) (“HRT with estrogen plus progestogen may or may not increase the risk of breast cancer, but the WHI did not establish that it does.”).  In any event, given the state of the science, most defendants would hedge their position on general causation even if they stopped short of saying it was not established.  Still, the validity concerns may cause us to have some doubts that the conclusions drawn from the WHI and other studies are truly “knowledge.”

Professor Guzelian has persuaded me that their indictment of Blaustein’s opinion on specific causation is correct, at least technically.  There are, to be sure, a few genetic causes of breast cancer, such as the BrCa 1, and 2, genes, which can cause breast cancer, and which, if present in a particular woman, would constitute an adequate description of the cause of that woman’s cancer.  Blaustein claimed that there is no generally accepted method for attributing an individual woman’s breast cancer to known causes, and Davidson and Guzelian are correct that Blaustein’s claim is, therefore, “simply false.”

Given how cursory and conclusory the trial court’s opinion is, Davidson and Guzelian’s derision is, however, relatively uncharitable.  We can probably credit the plaintiff’s counsel with sufficient entrepreneurial savvy to have not pressed the claims of a woman who had a known genetic cause of breast cancer.  And we can similarly credit the defense counsel with sufficient intelligence not to have overlooked the presence of such a gene if it were present.

With genetic causes taken out of the equation, Blaustein’s opinion seems fairly unremarkable.  Even if the criticism of the trial court’s refusal to preclude Dr. Blaustein’s testimony on general causation were correct under Federal Rule of Evidence 702, Davidson and Guzelian have failed to make their case against the trial court, and Dr. Blaustein, on specific causation.

Here is what Davidson and Guzelian have to say about Blaustein’s specific causation opinion:

“EBM has documented and catalogued the best practices regarding how to diagnose whether generally applicable evidence-based conclusions hold for specific patients.51 Moreover, even if in a specific case it were plausible to assert that it is impossible to reach a specific causation conclusion for a particular patient’s condition using the scientific method, that is very different than saying that there is no scientific method for analyzing specific causation. According to EBM’s strictures, Blaustein’s proposed blanket denial of the possibility of specific causation should have been precluded from his testimony.52”

Davidson at 757. The footnotes in this passage are to the section of an article on evidence-based toxicology, which deals with attribution of an adverse drug reaction.  Philip Guzelian et al., “Evidence-Based Toxicology: A Comprehensive Framework for Causation,” 24 Human & Experimental Toxicol. 161, 190-91 (Table 9) (2005) (presenting “an overview of evidence-based specific causation diagnostic criteria”). Putting aside the very substantial differences between cancer causation and the general run of adverse drug reactions, we can see that the proposed criteria for specific causation in the referenced article contain this extremely important criterion:

“No good alternative candidate (unexplained exacerbation or recurrence of underlying illness).”

Id.  Specific causation in a breast cancer case falls outside this criterion because most cases of breast cancer (with the exception of the genetic cases mentioned above) have no identifiable risk factor.  Dr. Blaustein’s opinion on specific causation — that there is no generally accepted method for attributing breast cancer to exogenous cause(s) — seems then exactly on point, even on the EBM criteria for specific causation urged by the authors.

In Cross, the trial court does not provide any insight into the basis for the plaintiffs’ challenge to Blaustein’s specific causation opinion, and I am aware of none.  The trial court does not give us any particulars of the plaintiff’s use of CHRT or development of breast cancer, and there is no suggestion that she had an extraordinarily high risk (say > 10-fold increase, which I have never seen reported, in any event).

The plaintiffs did not attempt to infer causation from risk.  Perhaps they thought better of it, or perhaps one of their testifying epidemiologists, Dr. Graham Colditz, refused to support such an inference:

“Knowledge that a factor is associated with increased risk of disease does not translate into the premise that a case of disease will be prevented if a specific individual eliminates exposure to that risk factor. Disease pathogenesis at the individual level is extremely complex. As Rose stated, a preventive measure that brings large benefits to the community offers little to each participating individual [3]. Accordingly, epidemiology must be harnessed to identify the population level strategies that will reduce the burden of illness.”

Graham A. Colditz, “From epidemiology to cancer prevention: implications for the 21st Century,” 18 Cancer Causes Control 117, 118 (2007).  Professor Colditz’ view is hardly unique; there are many similar refusals to base an inference of specific causation upon an increased risk, whether or not that increased risk is quantified as a relative risk greater than two.  The late David Freedman, who was the co-author of the chapters on statistics in all three editions of the Reference Manual on Scientific Evidence, was also a naysayer when it came to transmuting risk into cause:

“The scientific connection between specific causation and a relative risk of two is doubtful. *** Epidemiologic data cannot determine the probability of causation in any meaningful way because of individual differences.”

David Freedman & Philip Stark, “The Swine Flu Vaccine and Guillaine-Barré Syndrome:  A Case Study in Relative Risk and Specific Causation,” 64 Law & Contemporary Problems 49, 61 (2001).

The plaintiffs’ challenge to Blaustein’s claim that there was no “generally accepted” method for specific causal attribution took the form of advancing their own “method”:  differential diagnosis. At face value, the plaintiffs’ use of differential diagnosis to advance a claim of specific causation is “simply false.”  There was no dispute about diagnosis, and no differential diagnosis at issue.  Unfortunately, courts have permitted lawyers to corrupt the meaning of differential diagnosis and contend that it covers something akin to differential etiology.

Davidson and Guzelian, in their reference back to an earlier article on evidence-based toxicology, embrace differential etiology as a method of specific case attribution.  I agree that there is really no dispute about the logically validity of such reasoning, generally.  The logic of differential etiology is simple.  If you can specify all the known causes of a disease, and eliminate all but one cause, then you have ruled in the specific cause.  Logically, this is an iterative disjunctive syllogism, also known as the process of elimination.  The syllogism requires an exhaustive statement of disjuncts, with the negation of all but one:

A v B v C v D

~A and ~B and ~ C.

Therefore, D.

In “The Adventure of the Beryl Coronet,” Sir Arthur Conan Doyle had his famous detective, Sherlock Holmes, articulate this method in ordinary English, with a bit more flair:

“It is an old maxim of mine that when you have excluded the impossible, whatever remains, however improbable, must be the truth.”

Arthur Conan Doyle, The Penguin Complete Sherlock Holmes 315 (Penguin 1981). The process of elimination was a mainstay of Holmes’ forensic thought:

“Eliminate all other factors, and the one which remains must be the truth.”

“The Sign of the Four,” chap. 1 (“The Science of Deduction”), in Arthur Conan Doyle, The Penguin Complete Sherlock Holmes at 92 (Penguin 1981).

The problem of course is, for a disease such as breast cancer, is that one of the disjuncts has been, and will remain, for some time: the proposition that this case is “idiopathic” or “sporadic.” The plaintiffs in Cross did not advance any plausible method for eliminating this disjunct.  As a result, they can never arrive at a conclusion that CHRT was a cause of Ms. Cross’s breast cancer.  The closest they can get to their desired conclusion with this “method,” once they have eliminated genetic causes, is a conclusion that:

The case is idiopathic OR the case resulted from CHRT.

This conclusion is not really a conclusion at all, but an indeterminate statement, which would be quite unhelpful to the trier in deciding the case. Furthermore, as the case is described by the trial court’s opinion, the plaintiffs did not even attempt a quantification of the probability of each of these two disjuncts.  Thus, the plaintiffs failed to offer any substantial evidence that a jury could believe to find in their favor on specific causation.  The trial court was correct to reject the challenge to Dr. Blaustein’s specific causation opinion, but the court should have granted the defendants’ challenge to the plaintiffs’ expert witnesses, who had no method at all on the crucial element of specific causation.

Interestingly, one of the plaintiffs’ better arguments against Dr. Blaustein was that he was, as a clinician, unqualified to opine on causation.  Cross, *9.  The trial court did not elaborate on the argument other than to point out that plaintiffs had emphasized that Dr. Blaustein relied upon his “unquantifiable and untested clinical experience.” Cross, *10. The courts have been remarkably resistant to the argument that physicians are generally unqualified to interpret scientific evidence of causation.  Sadly, there is a good deal of empirical evidence to show that physicians are not particularly well trained in statistics or in interpreting clinical research.  See, e.g., Donna Windish, Stephen Huot, and Michael Green, “Medicine Residents’ Understanding of the Biostatics and Results in the Medical Literature,” 298 J. Am. Med. Ass’n 1010, 1010 (2007) (“Most residents in this study lacked the knowledge in biostatistics to interpret many of the results in published clinical research.”).

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Broadbent on the Relative Risk > 2 Argument

October 31st, 2012

Alex Broadbent, of the University of Johannesburg, Department of Philosophy, has published a paper that contributes to the debate over whether a relative risk (RR) greater than (>) two is irrelevant, helpful, necessary, or sufficient in inferring that an exposure more likely than not caused an individual claimant’s disease. Alex Broadbent, “Epidemiological Evidence in Proof of Specific Causation,” 17 Legal Theory 237 (2011) [cited as Broadbent].  I am indebted to his having called his paper to my attention. Professor Broadbent’s essay is clearly written, which is helpful in assessing the current use of the RR > 2 argument in judicial decisions.

General vs. Specific Causation

Broadbent carefully distinguishes between general and specific causation.  By focusing exclusively upon specific causation (and assuming that general causation is accepted), he avoids the frequent confusion over when RR > 2 might play a role in legal decisions. Broadbent also “sanitizes” his portrayal of RR by asking us to assume that “the RR is not due to anything other than the exposure.” Id. at 241. This is a BIG assumption and a tall order for observational epidemiologic evidence.  The study or studies that establishes the RR we are reasoning from must be free of bias and confounding. Id.  Broadbent does not mention, however, the statistical stability of the RR, which virtually always will be based upon a sample, and thus subject to the play of random error.  He sidesteps the need for statistical significance in comparing two proportions, but the most charitable interpretation of his paper requires us to assume further that the hypothetical RR from which we are reasoning is sufficiently statistically stable that random error, along with bias and confounding, can be also ruled out as likely explanations for the RR > 1.

Broadbent sets out to show that RR > 2 may, in certain circumstances, suffices to show specific causation, but he argues that RR > 2 is never logically necessary, and must never be required to support a claim of specific causation.  Broadbent at 237.  On the same page in which he states that epidemiologic evidence of increased risk is a “last resort,” Broadbent contradicts himself by stating RR > 2 evidence “must never be required,” and then, in an apparent about face, he argues:

“that far from being epistemically irrelevant, to achieve correct and just outcomes it is in fact mandatory to take (high-quality) epidemiological evidence into account in deciding specific causation. Failing to consider such evidence when it is available leads to error and injustice. The conclusion is that in certain circumstances epidemiological evidence of RR > 2 is not necessary to prove specific causation but that it is sufficient.”

Id. at 237 (emphasis added). I am not sure how epidemiologic evidence can be mandatory but never logically necessary, and something that we should never require.

Presumably, Broadbent is using “to prove” in its legal and colloquial sense, and not as a mathematician.  Let us also give Broadbent his assumptions of “high quality” epidemiologic studies, with established general causation, and ask why, and explore when and whether, RR > 2 is not necessary to show specific causation.

The Probability of Causation vs. The Fact of Causation

Broadbent notes that he is arguing against what he perceives to be Professor Haack’s rejection of probabilistic inference, which would suggest that epidemiologic evidence is “never sufficient to establish specific causation.” Id. at 239 & n.3 (citing Susan Haack, “Risky Business: Statistical Proof of Individual Causation,” in Causación y Atribucion de Responsabilidad (J. Beltran ed., forthcoming)). He correctly points out that sometimes the probabilistic inference is the only probative inference available to support specific causation.  His point, however, does not resolve the dispute; it suffices only to show that whether we allow the probabilistic inference may be outcome determinative in many lawsuits.  Broadbent characterizes Haack’s position as one of two “serious mistakes in judicial and academic literature on this topic.”  Broadbent at 239.  The other alleged mistake is the claim that RR > 2 is needed to show specific causation:

“What follows, I conclude, is that epidemiological evidence is relevant to the proof of specific causation. Epidemiological evidence says that a particular exposure causes a particular harm within a certain population. Importantly, it quantifies: it says how often the exposure causes the harm. However, its methods are limited: they measure only the net effect of the exposure, leaving open the possibility that the exposure is causing more harm than the epidemiological evidence suggests—but ruling out the possibility that it causes less. Accordingly I suggest that epidemiological evidence can be used to estimate a lower bound on the probability of causation but that no epidemiological measure can be required. Thus a relative risk (RR, defined in Section II) of greater than 2 can be used to prove causation when there is no other evidence; but RR < 2 does not disprove causation. Given high-quality epidemiological evidence, RR > 2 is sufficient for proof of specific causation when no other evidence is available but not necessary when other evidence is available.”

Some of this seems reasonable enough.  Contrary to the claims of authors such as Haack and Wright, Broadbent maintains that some RR evidence is relevant and indeed probative of specific causation.  In a tobacco lung cancer, with a plaintiff who has smoked three packs a day, for 50 years (and RR > 50), we can confidently attribute the lung cancer to smoking, and rest assured that background cosmic radiation did not likely play a substantial role. The RR quantifies the strength of the association, and it does lead us to a measure of “attributable risk” (AR), also known as the attributable fraction (AF):

AR = 1 – 1/RR.

So far, so good.

Among the perplexing statements above, however, Broadbent suggests that:

1. The methods of epidemiologic evidence measure only the net effect of the exposure.  Epidemiologic evidence (presumably the RR or other risk ratio) provides a lower bound on the probability of causation.  I take up this suggestion in discussing Broadbent’s distinction between the “excess fraction,” and the “etiologic fraction,” below.

2. A RR > 2 “can be used to prove causation when there is no other evidence; but RR < 2 does not disprove causation.” (My emphasis.) When an author is usually clear about his qualifications, and his language generally, it is distressing for him to start comparing apples to oranges.  Note that RR > 2 suffices “when there is no other evidence,” but the parallel statement about RR < 2 is not similarly qualified, and the statement about RR < 2 is framed in terms of disproof of causation. Even if the RR < 2 did not “disprove” specific causation, when there was no other evidence, it would not prove causation.  And if there is no other evidence, judgment for the defense must result. Broadbent fails to provide us a persuasive scenario in which a RR ≤ 2, with no other evidence, would support an inference of specific causation.

Etiological Fraction vs. Excess Fraction — Occam’s Disposable Razor

Broadbent warns that the expression “attributable risk” (AR or “attributable fraction,” AF) is potentially misleading.  The numerical calculation identifies the excess number of cases, above “expected” per base rate, and proceeds from there.  The AR thus identifies the “excess fraction,” and not the “etiological fraction,” which is the fraction of all cases in which exposure makes a contribution. Broadbent tells us that:

“Granted a sound causal inference, we can infer that all the excess cases are caused by the exposure. But we cannot infer that the remaining cases are not caused by the exposure. The etiologic fraction—the cases in which the exposure makes a causal contribution—could be larger. Roughly speaking, this is because, in the absence of substantive biological assumptions, it is possible that the exposure could contribute to cases that would have occurred12 even without the exposure.13 For example, it might be that smoking is a cause of lung cancer even among some of those who would have developed it anyway. The fact that a person would have developed lung cancer anyway does not offer automatic protection against the carcinogenic effects of cigarette smoke (a point we return to in Section IV).”

Id. at 241. In large measure here, Broadbent has adopted (and acknowledged) his borrowings from Professor Sander Greenland.  Id. at 242 n.11. The argument  still fails.  What Broadbent has interposed is a “theoretical possibility” that the exposure in question may contribute to those cases that would have occurred anyway.  Note that raising theoretical possibilities here now alters the hypothetical; Broadbent is no longer working from a hypothetical that we have a RR and no other evidence.  Even more important, we are left guessing what it means to say that an exposure causes some cases that would have occurred anyway.  If we accept the postulated new evidence at face value, we can say confidently that the exposure is not the “but for” cause of the case at issue.  Without sufficient evidence of “but for” causation, plaintiff will lose. Furthermore, we are being told to add a new fact to the hypothetical, namely that the non-excess cases are causally over-determined.  If this is the only additional new fact being added, a court might invoke the rule in Summers v. Tice, but even so, the defense will be entitled to a directed verdict if the RR < 2. (If the RR = 2, I suppose, the new fact, and the change in the controlling rule, might alter the result.)

Exposures that Cause Some and Prevent Some Cases of Disease

Broadbent raises yet another hypothetical possibility, which adds to, and materially alters,  his original hypothetical.  If the exposure in question, causes some cases, and prevents others, then the RR ≤ 2 will not permit us to infer that a given case is less likely than not the result of the exposure.  (Broadbent might have given an example of what he had in mind, from well-established biological causal relationships; I am skeptical that he would have found one that would have satisfactorily made his argument.) The bimodal distribution of causal effects is certainly not typical of biological processes, but even if we indulge the “possibility,” we are now firmly in the realm of speculation.  This is a perfectly acceptable realm for philosophers, but in court, we want evidence.  Assuming that the claimant could present such evidence, finders of fact would still founder because the new evidence would leave them guessing whether the claimant was a person who would have gotten the disease anyway, or got it because of the exposure, or even got it in spite of the exposure.

Many commentators who urge a “probability of [specific] causation” approach equate the probability of causation (PC) with the AR.  Broadbent argues that because of the possibility that some biological model results in the etiologic fraction exceeded the excess fraction, the usual equation of PC = AR, must be represented as an equality:

PC ≥ AR

While the point is logically unexceptional, Broadbent must concede that some other evidence, which supports and justifies the postulated biological model, is required to change the equality to an inequality.  If no other evidence besides the RR is available, we are left with the equality.  Broadbent tells us that the biological model “often” requires that the etiological fraction exceeds the excess fraction, but he never tells us how often, or how we would ascertain the margin of error.  Id. at 256.

Broadbent does not review any of the decided judicial cases to point out which ones involved biological models that invalidated the equality.  Doing so would be an important exercise because it might well show that even where PC ≥ AR, with a non-quantified upper bound, the plaintiff might still fail in presenting a prima facie case of specific causation.  Suppose the population RR for the exposure in question were 1.1, and we “know” (and are not merely speculating) that the etiological fraction > excess fraction.   Unless we know how much greater is the etiological fraction, such that we can recalculate the PC, then we are left agnostic about specific causation.

Broadbent treats us to several biological scenarios in which PC possibly is greater than AR.  All of these scenarios violate his starting premiss that we have a RR with no other evidence. For instance, Broadbent hypothesizes that exposure might accelerate onset of a disease.  Id. at 256. This biological model of acceleration can be established with the same epidemiologic evidence that established the RR for the population.  Epidemiologists will frequently look at time windows from onset of exposure to explore whether there is an acceleration of onset of cases in a younger age range that offsets a deficit later in the lives of the exposed population.  If there were firm evidence of such a phenomenon, then we would look to the RR within the relevant time window.  If the relevant RR ≤ 2, the biological model will have added nothing to the plaintiff’s case.

Broadbent cites Greenland for the proposition that PC > AR:

“We know of no cancer or other important chronic disease for which current biomedical knowledge allows one to exclude mechanisms that violate the assumptions needed to claim that PC = [AF].”

Id. at 259, quoting form Sander Greenland & James Robins, “Epidemiology, Justice, and the Probability of Causation,” 40 Jurimetrics J. 321, 325 (2000).  Here, not only has Broadbent postulated a mechanism that makes PC > AR, but he has shifted the burden of proof to the defense to exclude it!

The notion that the etiological fraction may exceed the excess fraction is an important caveat.  Courts and lawyers should take note.  It will not do, however, wave hands and exclaim that the RR > 2 is not a “litmus test,” and proceed to let any RR > 1, or even RR ≤ 1 support a verdict.  The biological models that may push the etiological fraction higher than the excess fraction can be tested, and quantified, with the same epidemiologic approaches that provided a risk ratio, in the first place.  Broadbent gives us an example of this sort of hand waving:

“Thus, for example, evidence that an exposure would be likely to aggravate an existing predisposition to the disease in question might suffice, along with RR between 1 and 2, to make it more likely than not that the claimant’s disease was caused by the exposure.”

Id. at 275. This is a remarkable, and unsupported claim.  The magnitude of the aggravation might still leave the RR ≤ 2.  What is needed is evidence that would allow quantification of the risk ratio in the scenario presented. Speculation will not do the trick; nor will speculation get the case to a jury, or support a verdict.

 

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Call for Evidence-Based Medicine in Medical Expert Opinions

October 30th, 2012 


Evidence-based medicine (EBM) seeks to put health care decision making on a firm epistemic foundation, rather than on the personal opinion of health care providers.  David Sackett, et al., “Evidence based medicine: what it is and what it isn’t,” 312 Brit. Med. J. 71 (1996).  EBM thus offers a therapeutic intervention, sometimes in the form of strong medicine, to the sloppy thinking, intuition, mothers’ hunches, and leveling of studies that remain prevalent in the Rule 702 gatekeeping of medical causation opinion testimony in courts.  There are some who have suggested that EBM addresses therapeutic interventions only, and not disease causation by exogenous substances or processes.  A very recent publication in the Tort Trial & Insurance Practice Law Journal provides a strong rebuttal to the naysayers and a clear articulation of the need now, more than ever, for greater acknowledgment of EBM in the evaluation of expert witness opinion testimony.  Terence M. Davidson & Christopher P. Guzelian, “Evidence-based Medicine (EBM): The (Only) Means for Distinguishing Knowledge of Medical Causation from Expert Opinion in the Courtroom,” 47 Tort Trial & Ins. Practice L. J. 741 (2012) [cited as Davidson].


Terence M. Davidson is a physician, a Professor of Surgery, and the Associate Dean for Continuing Medical Education at the University of California, San Diego School of Medicine.  Christopher P. Guzelian   is an Assistant Professor of Law at Thomas Jefferson School of Law, in San Diego, California. Davidson and Guzelian bring the Rule 702 discussion and debate back to the need for epistemic warrant, not glitz, glamour, hunches, prestige, and the like.  Their article is a valuable contribution, and the authors’ presentation and defense of EBM in the gatekeeping process is commendable.


There are some minor dissents I would offer.  For instance, in applying EBM principles to causation of harm assessments, we should recognize that there are asymmetries between determining therapeutic benefit and environmental or occupational harm.  Physicians, even those practicing EBM, may well recommend removal from a potentially toxic exposure because the very nature of their clinical judgment is often precautionary.  Tamraz v. BOC Group Inc., No. 1:04-CV-18948, 2008 WL 2796726 (N.D. Ohio July 18, 2008) (denying Rule 702 challenge to treating physician’s causation opinion), rev’d sub nom., Tamraz v. Lincoln Elec. Co., 620 F.3d 665, 673 (6th Cir. 2010) (carefully reviewing record of trial testimony of plaintiffs’ treating physician; reversing judgment for plaintiff based in substantial part upon treating physician’s speculative causal assessment created by plaintiffs’ counsel; “Getting the diagnosis right matters greatly to a treating physician, as a bungled diagnosis can lead to unnecessary procedures at best and death at worst. But with etiology, the same physician may often follow a precautionary principle: If a particular factor might cause a disease, and the factor is readily avoidable, why not advise the patient to avoid it? Such advice—telling a welder, say, to use a respirator—can do little harm, and might do a lot of good. This low threshold for making a decision serves well in the clinic but not in the courtroom, where decision requires not just an educated hunch but at least a preponderance of the evidence.”) (internal citations omitted), cert. denied, ___ U.S. ___ , 131 S. Ct. 2454, 2011 WL 863879 (2011).


The wisdom of the Tamraz decision (in the 6th Circuit) lies in its recognition of the asymmetries involved in medical decision making.  For most diseases, physicians rarely have to identify an etiology to select efficacious treatment.  This asymmetry affects the general – specific causation distinction.  A physician will want some epistemic warrant for the judgment that a therapy or medication is efficacious.  In other words, the physician needs to know that there is efficacy, even though the intervention may not be efficacious in every case.  If the risk ratio for an intervention (where the risk is cure of the disease or disorder), is greater than 1.0, and chance, bias, and confounding are eliminated as explanations for the observed efficacy, then that intervention likely goes into the physician’s therapeutic armamentarium.  The risk ratio, of course, need not be greater than two for the intervention to remain clinically attractive.  Furthermore, if the therapy is provided, and the patient improves, the determination whether therapy itself was efficacious is often not a pressing clinical matter.  After all, if the risk ratio was greater than one, but two or less, then the improvement may have been spontaneous and unrelated to therapy.


Davidson and Guzelian do not fully recognize this asymmetry, which leads the authors into error.  They give an example in which a defense expert witness proferred a personal opinion about general causation of breast cancer by post-menopausal hormone replacement therapy, which opinion is undermined and contradicted by a judgment reached with EBM principles.  See Cross v. Wyeth Pharm., Inc., 2011 U.S. Dist. LEXIS 89078, at *10 (M.D. Fla. Aug. 10, 2011).  Fair enough, but Davidson and Guzelian then claim that the errant defense expert had no basis for claiming that there was no generally accepted basis for “diagnosing specific medical causation.” Davidson at 757.  The authors go even further and claim that the defense expert’s statement is “simply false.” Id.


I would suggest that the authors have gotten this dead wrong.  In this sort of case, the plaintiff’s expert witness is usually the one casting about for a basis to support specific attribution.  The authors offer no basis for their judgment that the defense expert witness is wrong, or lacks a basis for his specific causation judgment. The poor, pilloried defense expert was, in the cited case, opining that there was no way to attribute a particular patient’s breast cancer to her prior use of post-menopausal hormone replacement therapy.  Putting aside the possibility of long-term use (with risk ratio greater than 2.0), the expert’s opinion is reasonable. General causation does not logically or practically imply specific causation; they are separate and distinct determinations.  Perhaps a high risk ratio might justify a probabilistic inference that the medication caused the specific patient’s breast cancer, but for many HRT-use factual scenarios, the appropriate risk ratio is two or less.  If there is some other method Davidson and Guzelian have in mind, they should say so. The authors miss an important point, which is that EBM sets out to provide a proper foundation for judgments of causality (whether of therapeutic benefit or harm), but it often does not have the epistemic foundation to provide a resolution of the individual causation issue. In medicine, there often is simply no need to do so.




One other nit.  The authors briefly discuss statistical significance, citing the Supreme Court’s recent foray into statistical theory.  Davidson at 747 & n. 14 (citing Matrixx Initiatives, Inc. v. Siracusano, 131 S. Ct. 1309, 1321 (2011)).  In their explanatory parenthetical, however, the authors describe the case as “holding that a lack of statistical significance in a pharmaceutical company’s results does not exempt the company from material disclosure requirements for reporting adverse events during product testing.”  Id.  


Matrixx Initiatives held no such thing; the Supreme Court was faced with an adequacy of pleadings case. No evidence was ever offered; nor was there any ruling on the reliability or insufficiency of evidence of causation. Matrixx Initiative’s attempt to import Rule 702 principles of reliability into a motion to dismiss on the pleadings was seriously misguided. Even assuming that statistical significance was necessary to causation, regulatory action did not require a showing of causality. Therefore, statistical significance was never necessary for the plaintiffs’ case. Second, the company’s argument that the adverse event reports at issue were “not statistically significant” was fallacious because adverse event reports, standing alone, could not be “statistically significant” or “insignificant.” The company would need to know the expected base rate for anosmia among Zicam users, and it would need to frame the adverse event reports in terms of an observed rate, so that the expected and observed rates could be compared against an assumption of no difference. Third, the class plaintiffs had alleged considerably more than just the adverse events, and the allegations taken together deserved the attention of a reasonable investor.  Bottom line:  the comments that the Court made about the lack of necessity for statistical significance were pure obiter dictum.


Highlighting these two issues in the Davidson & Guzelian article should not detract from the importance of the authors’ general enterprise. There is an aversion to examining the “epistemic warrant” behind opinion evidence in federal court gatekeeping.  Anything that treats that aversion, such as Davidson & Guzelian’s article, is good medicine.

				


				
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Origins of the Relative Risk of Two Argument for Specific Causation

				October 20th, 2012 

				

					
In an unpublished paper, which Professor Susan Haack has presented several times over the last few years, she has criticized the relative risk [RR] >2 argument.  In these presentations, Haack has argued that the use of RR to infer specific causation is an example of flawed “probabilism” in the law.  Susan Haack, “Risky Business:  Statistical Proof of Individual Causation,” in Jordi Ferrer Beltrán, ed., Casuación y atribución de responsibilidad (Madrid: Marcial Pons, forthcoming)[hereafter Risky Business]; Presentation at the Hastings Law School (Jan. 20, 2012);  Presentation at University of Girona (May 24, 2011).  Elsewhere, Haack has criticized the use of relative risks for inferring specific causation on logical grounds.  See, e.g., Susan Haack, “Warrant, Causation, and the Atomism of Evidence Law,” 5 Episteme 253, 261 (2008)[hereafter “Warrant“];  “Proving Causation: The Holism of Warrant and the Atomism of Daubert,” 4 J. Health & Biomedical Law 273, 304 (2008)[hereafter “Proving Causation“].  (See Schachtman, “On the Importance of Showing Relative Risks Greater Than Two – Haack’s Arguments” (May 23, 2012) (addressing errors in Haack’s analysis).


In “Risky Business,” Haack describes the RR > 2 argument as the creation of government lawyers from the litigation over claims of Guillain-Barré syndrome (GBS), by patients who had received swine flu vaccine.  Like her logical analyses, Haack’s historical description is erroneous.  The swine flu outbreak of 1976, indeed, had led to a federal governmental immunization program, which in turn generated claims that the flu vaccine caused GBS.  Litigation, of course, ensued.  The origins of the RR > 2 argument, however, predate this litigation.


GBS is an auto-immune disease of the nervous system.  The cause or causes of GBS are largely unknown. In the GBS vaccine cases, the government took the reasonable position that treating physicians or clinicians have little or nothing to contribute to understanding whether the swine-flu vaccine can cause GBS or whether the vaccine caused a particular patient’s case.  Cook v. United States, 545 F. Supp. 306 (N.D. Cal. 1982); Iglarsh v. United States, No. 79 C 2148, 1983 U.S. Dist. Lexis 10950 (N.D. Ill. Dec. 9, 1983).  The government did, however, concede that cases that arose within 10 weeks of vaccination were more likely than not related on the basis of surveillance data from the Centers for Disease Control.  After 10 weeks, the relative risk dropped to two or less, and thus the plaintiffs who developed GBS 10 weeks, or more, after immunization were more likely than not idiopathic cases (or at least non-vaccine cases).  See Michael D. Green, “The Impact of Daubert on Statistically Based Evidence in the United States,” Am. Stat. Ass’n, Proc. Comm. Stat. Epidem. 35, 37-38 (1998) (describing use of probabilistic evidence in the GBS cases).


Haack’s narrative of the evolution of the RR > 2 argument creates the impression that the government lawyers developed their defense out of thin air.  This impression is false.  By the time, the Cook and Iglarsh cases were litigated, the doubling of risk notion had been around for decades in the medical literature on radiation risks and effects.  Ionizing radiation had been shown to have genetic effects, including cancer risk, in the 1920’s.  By the time of the Manhattan project, radiation was a known cause of certain types of cancer. Although there was an obvious dose-response relationship between radiation and cancer, the nature of the relationship and the existence of thresholds were not well understood.  Medical scientists, aware that there were background mutations and genetic mistakes, thus resorted to a concept of a “doubling dose” to help isolate exposures that would likely be of concern.  See, e.g., Laurence L. Robbins, “Radiation Hazards:  III. Radiation Protection in Diagnostic Procedures,” 257 New Engl. J. Med. 922, 923 (1957) (discussing doubling dose in context of the medical use of radiation).


By 1960, the connection between “doubling dose” and a legal “more likely than not” evidentiary standard was discussed in the law review literature.  See, e.g., Samuel D. Estep, “Radiation Injuries and Statistics: The Need for a New Approach to Injury Litigation,” 59 Mich. L. Rev. 259 (1960).  If the doubling dose concept was not obviously important for specific causation previously, Professor Estep made it so in his lengthy law review article.  By 1960, the prospect of litigation over radiation-induced cancers, which had a baseline prevalence in the population, was a real threat.  Estep described the implications of the doubling dose:




“This number is known technically as the doubling dose and has great legal significance under existing proof rules.”




Id. at 271. 


* * *




“The more-probable-than-not test surely means simply that the trier of fact must find that the chances that defendant’s force caused the plaintiff’s injuries are at least slightly better than 50 percent; or, to put it the other way, that the chances that all other forces or causes together could have caused the injury are at least no greater than just short of 50 percent. Even if such an analysis is inapplicable to other types of cases, in those cases in which the only proof of causal connection is a statistical correlation between radiation dose and injury, the only just approach is to use a percentage formula. This is the case with all nonspecific injuries, including leukemia. Under existing rules the only fair place to draw the line is at 50 percent. These rules apply when the injury is already manifested as of the time of trial.”




Id. at 274.


The RR >2 argument was also percolating through the biostatistical and epidemiologic communities before the Cook and Iglarsh cases.  For instance, Philip Enterline,  a biostatistician at the University of Pittsburgh, specifically addressed the RR > 2 argument in a 1980 paper:




“The purpose of this paper is to illustrate how epidemiologic data can be used to make statements about causality in a particular case.”  


* * *


“In summary, while in a given instance we cannot attribute an individual case of disease to a particular occupational exposure, we can, based on epidemiologic observation, make a statement as to the probability that a particular occupational exposure was the cause.  Moreover, we can modify this probability by taking into consideration various aspects of a particular case.”  




Philip Enterline, “Attributability in the Face of Uncertainty,” 78 (Supp.) Chest 377, 377, 378 (1980).


About the time of the Cook case, the scientific media discussed Enterline’s suggestion for using epidemiologic data to infer specific causation.  See, e.g., Janet Raloff, “Compensating radiation victims,” 124 Science News 330 (1983).  Dr. David Lilienfeld, son of the well-known epidemiologist Abraham Lilienfeld, along with a lawyer, further popularized the use of attributable risk, derived from a relevant RR to quantify the probability that an individual case is causally related to an exposure of interest.  See David Lilienfeld & Bert Black, “The Epidemiologist in Court,” 123 Am. J. Epidem. 961, 963 (1986) (describing how a relative risk of 1.5 allows an inference of attributable risk of 33%, which means any individual case is less likely than not to causally related to the exposure). 


In the meanwhile, the RR argument picked up support from other professional epidemiologists.  In 1986, Dr. Otto Wong explained that for many common cancers, tied to multiple non-specific risk factors, probabilistic reasoning was the only way to make a specific attribution:




“In fact, all cancers have multiple causes. Furthermore, clinical features of cancer cases, caused by different risk factors, are seldom distinguishable from one another. Therefore, the only valid scientific way to address causation in a specific individual is through use of probability.”




Otto Wong, “Using Epidemiology to Determine Causation in Disease,” 3 Natural Resources & Env’t 20, 23 (1988).  The attributable risk [AR], derived from the RR, was the only rational link that could support attribution in many cases:




“For AR [attributable risk] to be greater than 50% (more likely than not), RR has to be greater than 2.  Thus, for any exposure with a RR of less than 2, the cancer cannot be attributed to that exposure according to the ‘more likely than not’ criterion.  That is, that cancer is ‘more likely than not’ a background case.”


***


“The epidemiologic measure for probability of causation is attributable risk, which can be used to determine whether a particular cause in an individual case meets the ‘more likely than not’ criterion.”




Id. at 24.


In 1988, three Canadian professional epidemiologists described the acceptance of the use of epidemiologic data to attribute bladder cancer cases in the aluminum industry. Ben Armstrong, Claude Tremblay, and Gilles Theriault, “Compensating Bladder Cancer Victims Employed in Aluminum Reduction Plants,” 30 J. Occup. Med. 771 (1988).


The use of the RR > 2 argument was not a phenomenon limited to defense counsel or defense-friendly expert witnesses.  In 1994, a significant textbook, edited by two occupational physicians who were then and now associated with plaintiffs’ causes, explicitly embraced the RR argument. Mark R. Cullen & Linda Rosenstock, “Principles and Practice of Occupational and Environmental Medicine,” chap. 1, in Linda Rosenstock & Marc Cullen, eds., Textbook of Clinical Occupational and Environmental Medicine 1 (Phila. 1994) [Cullen & Rosenstock].


The editors of this textbook were also the authors of the introductory chapter, which discussed the RR > 2 argument.  The first editor-author, Mark R. Cullen,  is now a Professor of Medicine in Stanford University’s School of Medicine.  He is a member of the Institute of Medicine (IOM). Professor Cullen has been involved in several litigations, almost always on the plaintiffs’ side.  In the welding fume litigation, Cullen worked on a plaintiff-sponsored study of Mississippi welders.  Linda Rosenstock was the director for the National Institute for Occupational Safety and Health (NIOSH) from 1994 through 2000. Dr. Rosenstock left NIOSH to become the dean of the University of California, Los Angeles School of Public Health.  She too is a member of the IOM.  Here is how Cullen and Rosenstock treat the RR > 2 argument in their textbook:




“In most workers’ compensation and legal settings, one of the physician’s roles in OEM [occupational and environmental medicine] practice is to establish whether or not it is probable (greater, than 50% likelihood) that the patient’s injury or disease is occupationally or environmentally related. Physicians, whose standards of scientific certainty are usually considerably higher than those of the legal field (for example, often at the 95% level that an observed association did not occur by chance), need to appreciate that a disease may be deemed work related (i.e., in legal jargon, with medical certainty or more probable than not) even when there remains significant uncertainty (up to 50%) about this judgment.


Epidemiologic or population-based data may be used to provide evidence of both the causal relationship between an exposure and an outcome and the likelihood that the exposure is related to the outcome in an individual case. *** Although they are not fully conclusive, well-performed and interpreted epidemiologic studies can play an important role in determining the work-relatedness of disease in a person, using some of the additional guidelines below.”


***


“The concept of attributable fraction, known by many names, including attributable risk and etiologic fraction, has particular utility in determining the likelihood of importance of a hazardous exposure. Although these numbers refer to risks in groups, as shown in the following section, reasonable extrapolations from these numbers can often be made about risks in individuals.”




Cullen & Rosenstock at 13. Cullen & Rosenstock work through an easy example and discuss its implications:




“For example, if all the members of a population are exposed to a factor, and there is a RR of 5 of disease in relation to the factor, then the PAR = 80% (= (5 – 1)/5 X 100). If exposures and other population characteristics are similar in a second population, then it also can be assumed that this factor will account for 80% of cases of the disease. A short conceptual leap can be made to individual attribution:  if an affected individual is similar (e.g., in age and gender) to those in the population and is similarly exposed (e.g., similar duration, intensity, and latency), then there is an 80% likelihood that the factor caused the disease in that individual.”


***


“By this reasoning of assuming that all in a population are exposed and the relative risk is greater that [sic] 2, then the PAR [population attributable risk] is greater than 50% (where PAR = (2 – 1)/2 X 100%).  Accordingly, if an affected individual is similar to the population in a study that has demonstrated a RR ≥  2, then the legal test (that there is a greater than 50% likelihood that the factor caused disease) can be met.”


***


“In cases in which the relative risks are stable (i.e., very narrow confidence intervals) and the patient is typical of the population studied, one can state these individual attributable risks with some assurance that they are valid estimates. When the studies are of limited power or give varying results, or if the patient’s exposure cannot be easily related to the study population., caution in using this method is appropriate.”




Cullen & Rosenstock at 13-14. Cullen and Rosenstock embraced probabilistic evidence because they understood that antipathy to probabilistic inference meant that there could be no rational basis for supporting recoveries in the face of known hazards that carried low relative risks (greater than 2).  The “conceptual leap” these authors described is small compared to the unbridgeable analytical gaps that result from trying to infer specific causation from clinicians’ hunches.

				


				
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Manganese Meta-Analysis Further Undermines Reference Manual’s Toxicology Chapter

				October 15th, 2012 

				

					
Last October, when the ink was still wet on the Reference Manual on Scientific Evidence (3d 2011), I dipped into the toxicology chapter only to find the treatment of a number of key issues to be partial and biased.  See “Toxicology for Judges – The New Reference Manual on Scientific Evidence” (Oct. 5, 2011).


The chapter, “Reference Guide on Toxicology,” was written by Professor Bernard D. Goldstein, of the University of Pittsburgh Graduate School of Public Health, and Mary Sue Henifin, a partner in the law firm of Buchanan Ingersoll, P.C.  In particular, I noted the authors’ conflicts of interest, both financial and ideological, which may have resulted in an incomplete and tendentious presentation of important concepts in the chapter.  Important concepts in toxicology, such as hormesis, were omitted completely from the chapter.  See, e.g., Mark P. Mattson and Edward J. Calabrese, eds., Hormesis: A Revolution in Biology, Toxicology and Medicine (N.Y. 2009); Curtis D. Klaassen, Casarett & Doull’s Toxicology: The Basic Science of Poisons 23 (7th ed. 2008) (“There is considerable evidence to suggest that some non-nutritional toxic substances may also impart beneficial or stimulatory effects at low doses but that, at higher doses, they produce adverse effects. This concept of “hormesis” was first described for radiation effects but may also pertain to most chemical responses.”)(internal citations omitted); Philip Wexler, et al., eds., 2 Encyclopedia of Toxicology 96 (2005) (“This type of dose–response relationship is observed in a phenomenon known as hormesis, with one explanation being that exposure to small amounts of a material can actually confer resistance to the agent before frank toxicity begins to appear following exposures to larger amounts.  However, analysis of the available mechanistic studies indicates that there is no single hormetic mechanism. In fact, there are numerous ways for biological systems to show hormetic-like biphasic dose–response relationship. Hormetic dose–response has emerged in recent years as a dose–response phenomenon of great interest in toxicology and risk assessment.”).


The financial conflicts are perhaps more readily appreciated.  Goldstein has testified in any number of so-called toxic tort cases, including several in which courts had excluded his testimony as being methodologically unreliable.  These cases are not cited in the Manual.  See, e.g., Parker v. Mobil Oil Corp., 7 N.Y.3d 434, 857 N.E.2d 1114, 824 N.Y.S.2d 584 (2006) (dismissing leukemia (AML) claim based upon claimed low-level benzene exposure from gasoline) , aff’g 16 A.D.3d 648 (App. Div. 2d Dep’t 2005); Exxon Corp. v. Makofski, 116 S.W.3d 176 (Tex.App.–Houston [14th Dist.] 2003, pet. denied) (benzene and ALL claim).


One of the disappointments of the toxicology chapter was its failure to remain neutral in substantive disputes, unless of course it could document its position against adversarial claims.  Table 1 in the chapter presents, without documentation or citation,  a “Sample of Selected Toxicological End Points and Examples of Agents of Concern in Humans.” Although many of the agent/disease outcome relationships in the table are well accepted, one was curiously unsupported at the time; namely the claim that manganese causes Parkinson’s disease (PD).  Reference Manual at 653.This tendentious claim undermines the Manual’s attempt to remain disinterested in what was then an ongoing litigation effort.  Last year, I noted that Goldstein’s scholarship was questionable at the time of publication because PD is generally accepted to have no known cause.  Claims that manganese can cause PD had been addressed in several reviews. See, e.g., Karin Wirdefeldt, Hans-Olaf Adami, Philip Cole, Dimitrios Trichopoulos, and Jack Mandel, “Epidemiology and etiology of Parkinson’s disease: a review of the evidence.  26 European J. Epidemiol. S1, S20-21 (2011); Tomas R. Guilarte, “Manganese and Parkinson’s Disease: A Critical Review and New Findings,” 118 Environ Health Perspect. 1071, 1078 (2010) (“The available evidence from human and non­human primate studies using behavioral, neuroimaging, neurochemical, and neuropathological end points provides strong sup­port to the hypothesis that, although excess levels of [manganese] accumulation in the brain results in an atypical form of parkinsonism, this clini­cal outcome is not associated with the degen­eration of nigrostriatal dopaminergic neurons as is the case in PD.”).


More recently, three neuro-epidemiologists have published a systematic review and meta-analysis of the available analytical epidemiologic studies.  What they found was an inverse association between welding, a trade that involves manganese fume exposure, and Parkinson’s disease. James Mortimer, Amy Borenstein, and Lorene Nelson, “Associations of welding and manganese exposure with Parkinson disease: Review and meta-analysis,” 79 Neurology 1174 (2012).


Here are the summary figures from the published meta-analysis:


 


The Fourth Edition should aim at a better integration of toxicology into the evolving science of human health effects.

				


				
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Hop on Pop Redux – Watson Case

				October 3rd, 2012 

				

					
Last month, Maxwell Kennerly of the Beasley Firm in Philadelphia posted about the Watson case in his blog.  See Max Kennerly, “The Science And Law Behind The $7 Million Microwave Popcorn Lung Jury Verdict” (Sept. 20, 2012).  This case has attracted a lot of attention, as it well should.  See “It’s Alimentary, My Dear Watson” (Sept. 20, 2012); and “Good’s Expert Witness Opinion Not Good Enough in Tenth Circuit” (Sept. 8, 2012).


Kennerly is correct that we should not lump the Watson case with other frivolous cases, such as the infamous McDonald’s hot-coffee spill case.  I suppose people can debate whether McDonald’s sold their coffee at too-high a temperature, but most civilized people can agree that McDonald’s makes bad coffee, and that everyone should be careful what they put between their legs, regardless of temperature.


Watson represents a paradigmatic tort case, involving exposure and diagnostic issues common to many toxic tort cases.  Mr. Watson was a mega-consumer of microwavable popcorn, flavored with diacetyl.  We can assume for discussion that diacetyl can cause bronchiolitis obliterans in factory workers who are exposed at relatively high levels.  There are, however, other causes, as well as idiopathic cases. Two uncertainties overlapped in the Watson case:  diagnosis and exposure assessment.  A treating physician pondered a differential diagnosis between hypersensitivity pneumonitis (HP) and bronchiolitis obliterans (BO).  As a carpet cleaner, Watson had occupational exposures that might well have caused HP.  Indeed, in August 2006, an open lung biopsy requested by his treating physicians, by pathologists at University Hospital, at the University of Colorado, interpreted Watson’s lung pathology as HP.  In 2010, Professor Eugene Mark, a well-known pulmonary pathologist at Harvard Medical School, interpreted the pathology as “in keeping with hypersensitivity pneumonitis.”  Although Dr. Mark was consulting for the defense in this case, he is not a frequent testifier, and his few forays have been almost always for plaintiffs in asbestos cancer cases.  To my understanding, none of the pathologists testified at the trial.


Despite the pathology report, Watson’s treating physician, Dr. Cecile Rose, advocated that the correct diagnosis was BO.  She wrote a letter to NIOSH, and other federal agencies, in which advanced her diagnosis, although she did not mention the hospital pathology.  Regulators and lawyers became involved.  NIOSH measurements of diacetyl in Watson’s home were below the level of detection.  Another set of diacetyl measurements taken by Watson’s legal team reported levels close to that of the industrial workers who sustained BO from workplace exposure to diacetyl.  The plaintiffs’ expert witnesses relied upon these measurements suggesting high exposure.  Just before trial, the defense renewed its Rule 702 motion, challenging the plaintiffs’ exposure level evidence.  The defendant’s motion sought preclusion of the plaintiffs’ expert witnesses’ reliance upon data generated by an Innova Model 1312 Photoacoustic Multi-Gas Monitor.  The court denied this motion, with leave to raise it at trial, and also precluded mention of the testing in front of the jury until the evidentiary matter is resolved. Order of June 22, 2012. I do not know how the court handled this important evidentiary issue at trial, and no analysis of the case is possible until this part of the story is told.


What can be said now, hypothetically, is that if the plaintiffs had no reliable evidence of high exposure, there was precious little in the exposure data to support Watson’s treating physician’s argument for BO, over HP.  The treating clinician did not settle on the BO diagnosis until she had the dubious exposure data. The pathology reports consistently favored the HP diagnosis.


Watson is the third consumer diacetyl case litigated to date.  The Newkirk case resulted in the 702 exclusion of plaintiffs’ expert witness, Dr. Egilman. Newkirk v. ConAgra Foods, Inc., 727 F. Supp. 2d 1006 (E.D.Wash. 2010), aff’d, 438 Fed.Appx. 607 (9th Cir. 2011).  See also Egilman v. ConAgra Foods, Inc., No. 10-35667, U.S. Court of Appeals for the Ninth Circuit (Sept. 5, 2012; unpublished memorandum) (refusing personal appeal of expert witness who claimed defamation and “wrongful exclusion” by district court).  A second case was tried to a jury verdict for the defense, and the appellate court upheld the judgment for the defense.  Khoury v. Conagra Foods, Inc., 368 S.W.3d 189 (Mo. Ct. App. 2012).


Kennerly argues that Watson had proof!  Referring to “evidence” as “proof” is a hyperbolic conceit of lawyers; I am sure have used the expression, as well.  Outside the legal world, proofs and demonstrations are the work of geometers and mathematicians; factual propositions are usually more modestly shown or suggested by evidence.  The “proof” that Kennerly cites is the testimony of Watson’s treating physician, Dr. Cecile Rose, MD, MPH, “a published expert and researcher of occupational pulmonary diseases,” who testified that the basis for her opinion:


“relates mainly to the fact that his lung disease has stabilized with the cessation of use of the product and exposure to the inhalants related with that product. The fact that there was no other causal explanation for his lung condition and the fact that the clinical findings in his lung disease were similar to those that occurred in workers who were exposed to butter flavoring also support that opinion.”


This is the same Dr. Rose who wrote to several federal regulatory agencies, to present a tendentiously abridged clinical case report of a patient with BO, who consumed thousands of bags of microwave diacetyl-flavored popcorn.  Even with the serious omissions of information, and the problematic exposure measurements, Dr. Rose hedged in her attribution:


“It is difficult to make a causal connection based on a single case report. We cannot be sure that this patient’s exposure to butter flavored microwave popcorn from daily heavy preparation has caused his lung disease. However, we have no other plausible explanation. Given the public health implications of this possibility, we wanted to alert you to our concerns.”


To be sure, this is nothing like the McDonald’s coffee-spill case.  This is a case of questioned and questionable science. Kennerly is correct; there is nothing frivolous about the Watson case.  If the diagnosis were correct, and the exposure measurements were accurate, this case would raise very serious public concerns for consumer exposure to diacetyl.  If the antecedents of the BO diagnosis are incorrect, then the judicial system has been snookered, again. The view from over 2,600 kilometers away suggests that the antecedent conditions were unlikely.

				


				
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Siracusano Dicta Infects Daubert Decisions

				September 22nd, 2012 

				

					
Gatekeeping is sometimes  intellectually challenging, but the challenge does not excuse sloppy thinking.  Understandably, judges will sometimes misunderstand the relevant science.  The process, however, allows the public and the scientific community to see what is happening in court cases, rather than allowing the critical scientific reasoning to be hidden in the black box of jury determinations.  This transparency can and should invite criticism, commentary, corrections, and consensus, when possible.


Bad legal reasoning is much harder to excuse.  The Supreme Court, in Matrixx Initiatives, Inc. v. Siracusano, 131 S. Ct. 1309 (2011), unanimously affirmed the reversal of a trial court’s Rule 12(b)(6) dismissal of a securities fraud class action.  The corporate defendant objected that the plaintiffs failed to plead statistical significance in alleging causation between Zicam and the loss of the sense of smell.  The Supreme Court, however, made clear that causation was not required to make out a claim of securities fraud.  It was, and would be, sufficient for the company’s product to have raised sufficient regulatory concerns, which in turn would bring regulatory scrutiny and action that would affect the product’s marketability.


The Supreme Court could have disposed of the essential issue in a two page per curiam opinion.  Instead the Court issued an opinion signed by Justice Sotomayor, who waxed carelessly about causation and statistical significance, which discussion was not necessary to the holding.  Not only was Justice Sotomayor’s discussion obiter dicta, but the dicta were demonstrably incorrect. Matrixx Unloaded (Mar. 29, 2011).


The errant dicta in Siracusano has already led one MDL court astray:


“While the defendant repeatedly harps on the importance of statistically significant data, the United States Supreme Court recently stated that ‘[a] lack of statistically significant data does not mean that medical experts have no reliable basis for inferring a causal link between a drug and adverse events …. medical experts rely on other evidence to establish an inference of causation.’ Matrixx Initiatives, Inc. v. Siracsano, 131 S.Ct. 1309, 1319 (2011).”


Memorandum Opinion and Order at 22, In re Chantix (Varenicline) Products Liability Litigation, MDL No. 2092, Case 2:09-cv-02039-IPJ Document 642 (N.D. Ala. Aug. 21, 2012)[hereafter cited as Chantix].  See Open Admissions for Expert Witnesses in Chantix Litigation.


It was only a matter of time before the Supreme Court’s dictum would be put to this predictably erroneous interpretation.  See “The Matrixx Oversold” (April 4, 2011).  Within two weeks, the error in Chantix propagated itself in another MDL case, with another trial court succumbing to the misleading dicta in Justice Sotomayor’s opinion.  See Memorandum in Support of Separate Pretrial Order No. 8933, Cheek v. Wyeth Pharm. Inc. (E.D.Pa. Aug. 30, 2012)(Bartle, J.).


In Cheek, Judge Harvey Bartle rejected a Rule 702 challenge to plaintiffs’ expert witness’s opinion.  I confess that I do not know enough about the expert witness’s opinion or the challenge to assess Judge Bartle’s conclusion.  Judge Bartle, however, invoked the Matrixx decision for the dubious proposition that:


“Daubert does not require that an expert opinion regarding causation be based on statistical evidence in order to be reliable. Matrixx Initiatives, Inc. v. Siracusano, 131 S. Ct. 1309, 1319 (2011). In fact, many courts have recognized that medical professionals often base their opinions on data other than statistical evidence from controlled clinical trials or epidemiological studies. Id. at 1320.”


Cheek at 16.  The Cheek decision is a welter of non-sequiturs.  The fact that in some instances statistical evidence is not necessary is hardly a warrant to excuse the lack of statistical evidence in every case. The truly disturbing gaps in reasoning, however, are not scientific, but legal. Siracusano was not a “Daubert” opinion; and Siracusano does not, and cannot, support the refusal to inquire whether statistical evidence was necessary in a causation opinion, in main part because causation was not at issue in Siracusano.


 


 


 


 


 


 


 

				


				
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Bipartisan Junk Science – Pork-Barrel Causation

				September 19th, 2012 

				

					
Despite the hand waving and finger pointing, junk science is embraced by both political parties in the United States, when it suits their purposes.  Both parties want to have God and science on their sides.


Congress created September 11th Victim Compensation Fund, 49 USC § 40101, also known as the James Zadroga 9/11 Health and Compensation Act (P.L. 111-347) (signed into law in January 2011). The Act was a touching acknowledgement of the dedication and sacrifices of first responders to the World Trade Center and Pentagon victims of an Islamic jihad. Being a victim, however, implies that the harm to be compensated was caused by the attack and its consequences.  The New York politicians soon learned that causality can be turned into a very malleable concept.


The law allocated over $4 billion for medical screening and treatment of fire fighters, policemen, emergency responders, and survivors.  Most of the covered conditions were acute onset respiratory and mental disorders caused by gases, fumes, dusts, and stresses, to which the workers were exposed.  The law also made the director of CDC’s National Institute for Occupational Safety and Health (NIOSH), the head of a World Trade Center Health Program, which could add new conditions to the list of compensable diseases, based upon a review of scientific evidence.


In September 2011, several New York congressmen and Senators petitioned the director, citing flimsy or non-existent scientific evidence, to add cancer to the list.  Senators Kirsten Gillibrand (D-NY) and Charles Schumer (D-NY), and Representatives Carolyn Maloney (D-NY), Jerrold Nadler (D-NY), Peter King (R-NY), Charles Rangel (D-NY), Nita Velazquez (D-NY), Michael Grimm (R-NY),  and Yvette Clark (D-NY), made their request, citing R. Zeig-Owens, M. Webber, C.B. Hall, et al., “Early assessment of cancer outcomes in New York City firefighters after the 9/11 attacks: an observational cohort study,” 378 Lancet 898 (2011).


This is pork barrel politics masquerading as sympathy for putative victims.  The Zeig-Owens study reported a non-statistically significant standardized incidence ratio for all cancer, of either 1.10 (95% CI 0.98–1.25), with a comparison group of the generalized U.S. male population, or 1.19 (95% CI 0.96–1.47), with unexposed firefighters as a comparison group, and corrected for possible surveillance bias.  Of course, given that there is no disease of cancer, the composite end point is not particularly meaningful.


Here are the authors’ (including Dr. Prezant’s) published interpretation of the data:


“We reported a modest excess of cancer cases in the WTC-exposed cohort. We remain cautious in our interpretation of this finding because the time since 9/11 is short for cancer outcomes, and the reported excess of cancers is not limited to specific organ types. As in any observational study, we cannot rule out the possibility that effects in the exposed group might be due to unidentified confounders.”


Zeig-Owens, at 898.  The Zeig-Owens study did not support any conclusions of causality between the workers’ exposures in 2001, and any type of cancer. See NIOSH Report Sets Up Run on September 11th Victim Compensation Fund by Non-Victims.


The WTC Health Program director requested recommendations from the program’s Scientific – Technical Advisory Committee (STAC), whether to add cancer generally, or any particular kind of cancer, to the Zadroga Act’s list of compensable conditions.  In April 2012, the STAC made its recommendations, essentially relying upon likely exposures, without any consideration of individual dose, duration, latency, and without any serious consideration of the available epidemiologic evidence.


The STAC claimed that the Lancet study reported statistically significant excesses of cancer; it did not. The Committee also failed to come to grips with the biological implausibility of excess rates of solid malignant tumors presenting within less than a decade since exposure:


“Given that cancer latencies for solid tumors average 20 years or more, it is noteworthy that the published FDNY study of fire fighters showed a statistically significant excess in all-site cancer with only 7 years of follow-up.”


In June 2012, NIOSH director, Dr. Howard, reported that he was inclined to accept the STAC’s recommendation, but held open a public comment period.  See Anemona Hartocollis, “Sept. 11 Health Fund Given Clearance to Cover Cancer,” N.Y. Times (June 8, 2012).  Not surprising, given the political pressure, the WTC Health Program director promulgated his final rule to include 50 types of cancer, including many that occurred less often than expected in the Zeig-Owens study.


This decision ignores appropriate scientific methodology for reaching causal conclusions.  Worse than its intellectual shabbiness, the decision insults the true victims of the jihad terrorism.


The rule is effective October 12, 2012.


 

				


				
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