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Rockefeller and McCarthy — The Rush from Responsibility

December 4th, 2013

William Rockefeller was the engineer who operated the Metro-North Railroad train at 83 mph around the Spuyten Dyvel curve, in the Bronx. The general speed limit is 70 mph, and the speed limit going into the curve is 30 mph. The train derailed, killing four passengers and injuring many more, some very seriously. Rockefeller told investigators that he had become “dazed,” whatever that means in the absence of some “dazing” event. Matt Flegenheimer & William K. Rashbaum, “Train Engineer Was Dazed Before Crash, Lawyer Says” (Dec. 3, 2013 ). George Orwell would have appreciated the slippery and soul-less use of the passive voice. Who did the dazing?

Jeffrey P. Chartier, Rockefeller’s lawyer, described his client as suffering from “highway hypnosis.” Chartier, testifying for his client, claimed that Rockefeller had lost concentration only momentarily, and that he was “extremely remorseful.” Metro-North trains are pretty substantial trains, not the sort that can accelerate momentarily from 30 to 82 mph.

Rockefeller is a member of the Association of Commuter Rail Employees, and so, of course, his union representative, Anthony Bottalico, had to weigh in on the issue. Bottalico casually mentioned that Rockefeller had described himself as having nodded off before the derailment. When pressed, Bottaclico realized his error in acknowledging responsibility, and he quickly changed up:

“People use the word ‘zoned out,’ ‘nod,’ ‘fell asleep,’ … I’m not a sleep expert.”

Bottalico’s indiscretion, in speaking to the media about a pending investigation (and trying to spin the facts to exculpate the union engineer) led the safety board to remove the union as a party to the investigation.

The search for responsibility is part of our human condition. Legal categories often drive the search. In occupational exposure cases, employers have tort immunity by virtue of workman’s compensation immunity. The Depression-era bargain between labor and management on workplace injuries pushes our legal system, and the litigation industry, to place responsibility on remote vendors of products and raw materials to the workplace, despite their lack of control over the dissemination of information on the job. In most so-called sophisticated intermediary cases, the accident or injury would not have occurred at all had the employer and the employees done their respective jobs with respect to providing a safe workplace.

In the Spuyten Duyvil crash, Rockefeller’s lawyer and rail safety pundits suggest that automatic systems might have prevented the derailment. The hard fact remains, however, that Rockefeller was the most important link in the causal chain. He was the “least expensive” means to avoid the disaster because it was his job and his responsibility to do so. Had Rockefeller simply done his job, four people killed in the crash would be alive today. And many more would not be crippled and in pain.

In today’s New York Times, Joe Nocera muses about how Long Island Congresswoman Carolyn McCarthy, was diagnosed with lung cancer. McCarthy, who is 69 years old, was a life-long cigarette smoker, yet in her court filings she refers to her lung cancer as her asbestos disease. Joe Nocera, “The Asbestos Scam” N.Y. Times (Dec. 3, 2013). We live in a free country (well, sort of free) and people should be free to deceive themselves and indulge their superstitions. But surely we can draw the line at deceiving others with such nonsense. McCarthy was never an asbestos insulator or an asbestos-exposed tradesperson. McCarthy’s lawyer, supposedly told The New York Post that “it has been conclusively proven that cigarette smoking and asbestos exposure act synergistically to cause lung cancer.”

Nocera points out that in fact it has not. Even Selikoff himself, who did so much to perpetuate a theory of multiplicative, synergistic reactivity, wrote that his insulator cohort synergistic risk estimates could not be extrapolated to other exposures (such as the evanescent household exposures alleged by Congresswoman McCarthy):

“These particular figures apply to the particular groups of asbestos workers in this study. The net synergistic effect would not have been the same if their smoking habits had been different; and it probably would have been different if their lapsed time from first exposure to asbestos dust had been different or if the amount of asbestos dust they had inhaled had been different.”

Selikoff, et al., “Asbestos Exposure, Cigarette Smoking and Death Rates,” 330 Ann. N.Y. Acad. Sci. at 487 (1979). Despite Selikoff’s atypical care, his colleagues who carried the Mt. Sinai banner into courtrooms all around this country, glibly ignored his qualification. See also “Irving Selikoff and the Right to Peaceful Dissembling.” Of course, when Selikoff’s heirs updated his insulator study, they did not find evidence of interaction even for insulators who lacked sufficiently heavy exposure to cause asbestosis. Steve Markowitz, Stephen Levin, Albert Miller, and Alfredo Morabia, “Asbestos, Asbestosis, Smoking and Lung Cancer: New Findings from the North American Insulator Cohort,” Am. J. Respir. & Critical Care Med. (2013). See “The Mt. Sinai Catechism” (June 7, 2013). I doubt that these qualifications will find their way into the reporting of The New York Post.

Ultimately, Irving Selikoff and his heirs helped create a litigation industry that has placed responsibility for asbestos disease on vendors, not employers, and completely out of proportion to any realistic appraisal of traditional tort law. Rockefeller and McCarthy, and Selikoff (and the litigation industry he helped to start) all illustrate the misallocation of responsibility for avoidable human suffering. Denialism is where you find it.

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Christopher Bryson and the Problem of Political Science

October 12th, 2013

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

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

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

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

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

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

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

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

* * *

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

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

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

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

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

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Harkonen’s Appeal Updated

October 9th, 2013

The Solicitor General’s office has obtained yet another extension in which to file its opposition to Dr. Harkonen’s petition for a writ of certiorari. The new due date is November 8, 2013.

This week, Nature published a news article on the Harkonen case. See Ewen Callaway, “Uncertainty on trial,” 502 Nature 17 (2013). Mr. Calloway’s story accurately recounts that Thomas Fleming, a biostatistician at the University of Washington, chaired the data safety monitoring board for the InterMune trial, and that he had told Dr. Harkonen and others at InterMune that he, Fleming, believed that the press release was misleading. But this “fact” simply represents that Fleming disagreed with the causal inference of efficacy. His opinion might well have been correct, but it did not make Dr. Harkonen’s press release “demonstrably” false. Overstating confidence in a conclusion may be the occasion for disputing the evidentiary warrant for the conclusion, but it does not make the speaker a liar.

Calloway also reports that the government believed that documents suggested that there had been off-label promotion of interferon γ-1b, but of course, the jury acquitted Dr. Harkonen of mislabeling. Calloway’s recitation of these discredited allegations, however, provide important context for why the federal government continues to overreach by pressing its opposition to Dr. Harkonen’s appeal on the conviction for criminal wire fraud.

Mr. Calloway notes that there were “statisticians, clinical researchers and legal scholars” who criticized the judgment of conviction on grounds that it rested upon misinterpretations and misunderstandings of statistics, and that it could criminalize much expert witness testimony, grant applications, and article submissions. But Mr. Calloway’s presentation is subtly biased. He fails to identify those “statisticians, clinical researchers and legal scholars,” other than a few whom he then impugns as having been “compensated” by the defense.

He quotes Stanford Professor Steven Goodman as filing a brief stating that:

“You don’t want to have on the books a conviction for a practice that many scientists do, and in fact think is critical to medical research… .”

Calloway errs in suggesting that Professor Goodman was a brief writer rather than an affiant. Dr. Zibrak, a pulmonary physician is quoted, with the note that he was compensated to tell other physicians about his clinical experience with interferon γ-1b in patients with idiopathic pulmonary fibrosis. By playing the “compensation card,” Calloway tries to diminish the force of Goodman’s and Zibrak’s substantive arguments. This sly attempt, however, is blunted by the significant number of legal scholars and scientists who filed amicus briefs without compensation. More important, the attempt is irrelevant to the issues in the case.

MISLEADING REPORTING

Calloway described the trial as showing that only “slightly fewer” patients had died on interferon γ-1b than on placebo, but that the difference was not statistically significant “because the probability that it was not due to the drug was greater than 5%, a widely accepted statistical threshold.” Well, the p-value was 0.08 on the intent-to-treat analysis, and 0.055 on the per-protocol analysis. When the investigators published a more sophisticated time-to-event analysis in the New England Journal of Medicine, their reported “hazard ratio for death in the interferon gamma-1b group, as compared with the placebo group, was 0.3 (95 percent confidence interval, 0.1 to 0.9).” Raghu et al. N. Engl. J. Med. 350, 125–133; 2004 (for the entire trial, not the “controversial” subgroup). Calloway notes the publication of the results, but fails to inform the Nature readers of this hazard ratio or the confidence interval. Some might say that Mr. Calloway misled readers by inaptly describing this hazard ratio as “slightly fewer” deaths on interferon γ-1b than placebo, and by failing to provide all the pertinent information.

Oh; wait. Is failure to present all the facts, fraud???

TRANSPOSITION FALLACY

Perhaps more ironic was that Mr. Calloway’s interpretation of statistical significance is wrong. The p-value is not the “probability that it was not due to the drug” or the probability that the null hypothesis is true. Good thing that Mr. Calloway does not live in the United States where statistical errors of this sort can be a criminal offense.

The Nature news story quoted Gordon Guyatt, from McMaster University, who thinks that Dr. Harkonen skewed the findings:

“This guy gave a very unbalanced presentation; whether it is sufficiently unbalanced that you should send him to jail, I don’t know… .”

But the data were all accurately presented; it was the use of the verb “demonstrate,” which triggered the prosecution. And it was hardly a “presentation”; it was a press release, which clearly communicated that a presentation was forthcoming within a couple of weeks at a scientific conference.

The story also cites Patricia Zettler, a former FDA attorney, who now teaches at Stanford Law School, for her doubts that the case will matter to most scientists. See also Zettle, “U.S. v. Harkonen: Should Scientists Worry About Being Prosecuted for How They Interpret Their Research Results?” (Oct. 7, 2013). If her prediction is correct, then this is a sad commentary on the scientific community. Ms. Zettler suggests that the Supreme Court is likely to deny the petition, and leave Dr. Harkonen’s conviction in place, and that this denial will not seriously affect scientific discourse. If this suggestion is true, then courts will have acquiesced in a very selective prosecution, given the widespread prevalence of the statistical reporting practices that were on trial here.

As much as everyone would like to see editors, scientists, governments, companies, and universities held to higher standards in science reporting, criminalizing the commonplace because the speaker is an unpopular scientist who has a commercial, as well as a scientific, interest is profoundly disturbing. Ultimately, all scientists, from private or public sectors, from academic or non-academic institutions, have financial or reputational interests to be advanced in their communication of scientific results.

The irony is that many federal judges would not exclude an expert witness who would testify under oath to a conclusion based upon much weaker evidence than Dr. Harkonen presented in a press release, and which announced a much fuller discussion at an upcoming scientific conference in a couple of weeks. If Ms. Zettler is correct, it will be much more difficult for federal and state trial judges to reject challenges to expert witness testimony based upon statistically “non-significant” results, with the old “goes to the weight, not the admissibility” excuse.

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Bradford Hill on Statistical Methods

September 24th, 2013

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

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

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

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

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

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

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

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

Bradford Hill at 299.

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

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

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

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

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

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

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

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

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

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

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

Id. at 10 (emphasis added).

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Do English Judges Diss Epidemiology?

September 13th, 2013

As noted the other day, Claire McIvor, a senior lecturer, at the Birmingham Law School, has published an interesting U.K. perspective on the use of epidemiologic and statistical evidence in health-outcome litigation. See “Debunking some judicial myths about epidemiology and its relevance to UK tort law,” in 21 Med. Law Rev. (2013), in press.

Ms. McIvor criticizes one case in particular for what she argues is an inappropriate dismissal of epidemiologic evidence as presented by an epidemiologist. Novartis Grimsby Ltd. v. Cookson, [2007] EWCA Civ 1261.

The pursuer, Cookson, worked for Novartis Grimsby, at its factory that manufactured dyes, including azo dyes, from 1964, until 2001, when he developed bladder cancer. Cookson also chose to be exposed to various carcinogens as a personal lifestyle; he smoked cigarettes, 1/2 to one pack per day, for about 20 years, before quitting around 1980.

Cookson sued Novartis on allegations that he was overexposed to various aromatic amines[1], some of which are known to cause bladder cancer. Novartis had previously paid such claims, but it contested Mr. Cookson’s case because of its belief that his workplace exposures had not been excessive, and that his past smoking habit more likely explained his cancer. Both sides called physician expert witnesses, urologists, who both agreed that smoking and the aromatic amines could cause bladder cancer, but disagreed as to what caused Mr. Cookson’s disease.

Given the contest on causation, the two urologists agreed that the input of an epidemiologist, jointly instructed, would be helpful. Now how quaint is that, for both sides to agree upon an expert witness? Most lawyers in the United States would think it malpractice to engage in such a practice.

Professor Ray Cartwright, an epidemiologist who had published on the causes of bladder cancer, was the jointly instructed witness. A PubMed search for articles written by Cartwright on bladder cancer is set out below, and suggests that he was an appropriate choice, ex ante, at any rate.

Cartwright reviewed the epidemiologic literature, including some of his own studies. Cartwright’s report disappointed the plaintiff, however, when he opined that the workplace aromatic amine exposure was slight and posed only a low risk compared to the smoking. In assessing Cookson’s workplace exposure, Cartwright relied upon the exposure estimates of the parties’ industrial hygienists, and based his causal attribution upon an assessment that exposures were low. Later, when plaintiff’s counsel showed that Cartwright misinterpreted some of the exposure data, Cartwright revised his report, but maintained that Cookson’s cancer was caused by smoking.

Professor Cartwright’s misstep on exposure probably diminished the strength of his opinion in the eyes of the trial judge, who ruled for the plaintiff. Ms. McIvor seems to believe that this ruling improperly elevated clinical testimony over epidemiologic testimony, and credited “personalized probabilities” of the plaintiff’s testifying urologist, who attributed the cancer 20–25% to smoking, versus 70–75% to workplace exposures, and who opined that the workplace more than doubled the risk level that Cookson would have had had he never worked at the Novartis factory. Novartis Grimsby Ltd. at 48.

Novartis appealed, on grounds that included an allegation of error in equating fact of exposure with causation of the bladder cancer. Speaking for a unanimous England and Wales Court of Appeal, Lady Justice Smith dismissed the appeal, including its challenge to the medical causation issues. Contrary to Ms. McIvor, however, the appellate court’s decision gave due weight to the epidemiologist, but found that the epidemiologic evidence was accessible to, and interpretable by, the clinicians. Although neither the appellate decision nor McIvor reviewed the actual epidemiologic evidence, several studies suggest that the relative risks for benzidine-derived dyes are greater than for smoking, and especially the risk for former smokers. The judicial decision flowed not from improvidently dismissing epidemiologic evidence, or testimony by an epidemiologist, but from relying upon epidemiologic evidence marshaled by the plaintiff, through his urologist.[2]

Both sides agreed that smoking could cause bladder cancer, but they also had to agree that the risk of bladder cancer wanes after smoking cessation. Unfortunately, the Court of Appeal did not review the evidence, but the Surgeon General’s Reports note that cessation reduces risk by half after only a few years. Wynder and Stellman (1977) and Wynder and Goldsmith (1977) suggest that the risk returns to baseline after 15 years of abstinence. A study by Cartwright himself suggested the return to baseline in six years, although other studies (by Iscovich; Howe; Vineis; Hartge; and Burch) suggested an initial decline, followed by a persistent increased risk even beyond 15 years of abstinence.

Lady Justice Smith declared herself perplexed by these data, which seemed to be at odds with the notion that bladder cancer develops after 20 or more years latency:

“I myself have found it hard to understand how the passage of time after stopping smoking could result in a reduced risk of developing the disease if the aetiology of the disease is that the cancer begins at the time of exposure but does not manifest itself until later. However, as I have said, this issue was not fully explored in evidence and both experts agreed that the risk of developing bladder cancer from smoking decreased after smoking ceased.”

Novartis Grimsby Ltd. at 45.

Clearly though, it was not helpful to have Cartwright contradicted by the data in his own study. Although the higher aromatic amine exposures occurred early in the plaintiff’s work career, Cookson continued to have some exposure up until the time of his diagnosis in 2001. Professor Cartwright may well have been further undermined by the lack of any “time windows” in the occupational epidemiology, which would have supported a similar argument of declining risk from the more intense occupational exposure in the 1960’s. The absence of such evidence for benzidine, compared with the evidence of latency and post-cessation declining risk for smoking, clearly hurt the employer’s case. This imbalance in the evidence clearly helps to explain and support the courts’ rejection of Cartwright’s testimony.

Given the epidemiologic evidence, it is not at all clear that the plaintiff’s testifying urologist’s opinion that smoking contributed 25%-30%, whereas aromatic amines contributed 70%-75%, was merely a subjective or personal probability. Smoking is associated with a two- to three-fold increase in risk in prospective studies, but Cookson was 20 years post-cessation. His aromatic amine dyestuff exposure, which carries a much higher relative risk for bladder cancer, continued through till the end of his work tenure. See “Dyes metabolized to benzidine,” in IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Volume 100F (WHO 2012).

Cookson’s bladder cancer might have been a “background” case, or a result of both smoking and aromatic amine exposure, or a result of one or the other contested causes. There appeared to be no serious evidence of synergy. Given the studies at issue, the plaintiff’s testifying urologist’s opinion may well have been a reasoned analysis of the epidemiologic evidence. The epidemiologist’s opinion, on the other hand, was clearly undermined by the facts of smoking cessation, and an initial error in exposure estimation. Novartis’ counsel argued that Cartwright was the “real expert” on the issue of attribution, but Cartwright’s opinion was lacking important foundational facts, and there was no argument that Mr. Barnard, the plaintiff’s urologist, had erred in interpreting the epidemiologic data. Novartis Grimsby Ltd. at 56. The real “expert” was in the data, and there was no showing (at least in the published opinion) that the clinician, Mr. Barnard, misunderstood or distorted the epidemiologic data. In this respect, the Novartis Grimsby case is very different from the Milward case, in which a plaintiff’s toxicologist mistreated, misanalyzed, and misrepresented epidemiologic studies on benzene.

Lady Justice Smith rejected the appellant’s criticism of the trial judge’s weighting Mr. Barnard’s opinion over Professor Cartwright’s:

“The proposition that a clinician is not capable of fully understanding the published epidemiological literature on the causation of a condition within his own specialty seems unsustainable and would, I think, surprise many clinicians and epidemiologists. In my view, it was clear from his detailed reports on causation that Mr. Barnard was familiar with the published work and he was also able to discuss it intelligently when giving evidence. The Recorder was plainly of that view. As for the suggestion that Mr. Barnard was too ready to assume that working for the appellant created an increased risk, this was a good ‘jury point’ but, if it did not appeal to the Recorder, that was an end to it.”

Novartis Grimsby Ltd. at 57.

Although Ms. McIvor is correct to be concerned with the court’s eager over-generalization about the ability of clinicians to understanding of epidemiologic studies, there was little suggestion that Mr. Barnard had tripped up, and there was a good deal to suggest that Professor Cartwright’s opinion was lacking on essential issues. Admittedly, this impression may have been created by selective reporting by the Court of Appeal. I have not seen the record or the briefs, but Ms. McIvor has not cited anything from those sources.

Mr. Barnard, the plaintiff’s urologist, further testified that the “occupational exposure had more than doubled the risk due to smoking.” Novartis Grimsby Ltd. at 53. The Court of Appeal thus found it easy to affirm the verdict that Cookson had shown that his workplace exposure was the “but for” cause of his cancer. Of course, the Court of Appeal here accepted evidence of risk and relative risk as showing causation, a dubious proposition. Novartis Grimsby Ltd. at 67. And the Court of Appeal, distinguishing a pneumoconiosis case, further pronounced that the bladder cancer injury was “indivisible,” and thus not capable of an apportionment because neither exposure could be said to make the disease more severe. The Court could have said, if it yielded to its own risk as causation rationale, that both exposures made the cancer more likely, and the occupational exposure contributed to this overall risk three times as much as the plaintiff’s smoking. In Justice Lady Smith’s words:

“The natural inference to draw from the finding of fact that the occupational exposure was 70% of the total is that, if it had not been for the occupational exposure, the respondent would not have developed bladder cancer. In terms of risk, if occupational exposure more than doubles the risk due to smoking, it must, as a matter of logic, be probable that the disease was caused by the former.”

Novartis Grimsby Ltd. at 74.

The Court of Appeal’s opinion was thus consistent with its own commitment to the conflation of risk with causation, a conflation that may well be objectionable, but does not seem to be the basis for Ms. McIvor’s objections to the Novartis decision. Of course, a remand with directions to apportion would have a perfectly logical and consistent result with the insistence that risk be substituted for causation in supporting the verdict below.

Publications of Professor Cartwright on Bladder Cancer from National Library of Medicine Database

1: Subramonian K, Cartwright RA, Harnden P, Harrison SC. Bladder cancer in patients with spinal cord injuries. BJU Int. 2004 Apr;93(6):739-43. PubMed PMID: 15049983.

2: Cartwright RA. Bladder cancer screening in the United Kingdom. J Occup Med. 1990 Sep;32(9):878-80. PubMed PMID: 2074512.

3: Cuzick J, Babiker A, De Stavola BL, McCance D, Cartwright R, Glashan RW. Palmar keratoses in family members of individuals with bladder cancer. J Clin Epidemiol. 1990;43(12):1421-6. PubMed PMID: 2147716.

4: Philip PA, Fitzgerald DL, Cartwright RA, Peake MD, Rogers HJ. Polymorphic N-acetylation capacity in lung cancer. Carcinogenesis. 1988 Mar;9(3):491-3. PubMed PMID: 3345587.

5: Cartwright RA. Screening workers exposed to suspect bladder carcinogens. J Occup Med. 1986 Oct;28(10):1017-9. PubMed PMID: 3772536.

6: Boyko RW, Cartwright RA, Glashan RW. Bladder cancer in dye manufacturing workers. J Occup Med. 1985 Nov;27(11):799-803. PubMed PMID: 4067684.

7: Cartwright RA, Philip PA, Rogers HJ, Glashan RW. Genetically determined debrisoquine oxidation capacity in bladder cancer. Carcinogenesis. 1984 Sep;5(9):1191-2. PubMed PMID: 6467507.

8: Cartwright RA, Glashan RW. Palmar keratoses and bladder cancer. Lancet. 1984 Mar 10;1(8376):563. PubMed PMID: 6142276.

9: Cartwright RA, Adib R, Appleyard I, Glashan RW, Gray B, Hamilton-Stewart PA, Robinson M, Barham-Hall D. Cigarette smoking and bladder cancer: an epidemiological inquiry in West Yorkshire. J Epidemiol Community Health. 1983

Dec;37(4):256-63. PubMed PMID: 6655413; PubMed Central PMCID: PMC1052920.

10: Cartwright RA, Adib R, Appleyard I, Glashan RW, Richards B, Robinson MR, Sunderland E, Barham-Hall D. ABO, MNSs and rhesus blood groups in bladder cancer. Br J Urol. 1983 Aug;55(4):377-81. PubMed PMID: 6411162.

11: Cartwright RA, Adib R, Appleyard I, Coxon JG, Glashan RW, Richards B, Robinson MR, Sunderland E, Barham-Hall D. Ten genetic polymorphisms in bladder cancer. J Med Genet. 1983 Apr;20(2):112-6. PubMed PMID: 6221102; PubMed Central PMCID: PMC1049011.

12: Cartwright RA. Historical and modern epidemiological studies on populations exposed to N-substituted aryl compounds. Environ Health Perspect. 1983 Mar;49:13-9. PubMed PMID: 6339220; PubMed Central PMCID: PMC1569142.

13: Cartwright RA, Robinson MR, Glashan RW, Gray BK, Hamilton-Stewart P, Cartwright SC, Barham-Hall D. Does the use of stained maggots present a risk of bladder cancer to coarse fishermen? Carcinogenesis. 1983;4(1):111-3. PubMed PMID: 6821882.

14: Cartwright RA, Glashan RW, Rogers HJ, Ahmad RA, Barham-Hall D, Higgins E, Kahn MA. Role of N-acetyltransferase phenotypes in bladder carcinogenesis: a pharmacogenetic epidemiological approach to bladder cancer. Lancet. 1982 Oct 16;2(8303):842-5. PubMed PMID: 6126711.

15: Garner RC, Mould AJ, Lindsay-Smith V, Cartwright RA, Richards B. Mutagenic urine from bladder cancer patients. Lancet. 1982 Aug 14;2(8294):389. PubMed PMID: 6124790.

16: Cartwright R. Occupational bladder cancer and cigarette smoking in West Yorkshire. Scand J Work Environ Health. 1982;8 Suppl 1:79-82. PubMed PMID: 7100861.

17: Glashan RW, Cartwright RA. Occupational bladder cancer and cigarette smoking in West Yorkshire. Br J Urol. 1981 Dec;53(6):602-4. PubMed PMID: 7317749.

18: Cartwright RA, Gadian T, Garland JB, Bernard SM. The influence of malignant cell cytology screening on the survival of industrial bladder cancer cases. J Epidemiol Community Health. 1981 Mar;35(1):35-8. PubMed PMID: 7264531; PubMed Central PMCID: PMC1052117.

19: Cartwright RA, Adib R, Glashan R, Gray BK. The epidemiology of bladder cancer in West Yorkshire. A preliminary report on non-occupational aetiologies. Carcinogenesis. 1981;2(4):343-7. PubMed PMID: 7273315.

20: Cartwright RA, Glashan RW, Gray B. Survival of transitional cell carcinoma cases in 2 Yorkshire centres. Br J Urol. 1980 Dec;52(6):497-9. PubMed PMID: 7459578.

21: Cartwright RA, Bernard SM, Glashan RW, Gray BK. Bladder cancer amongst dye users. Lancet. 1979 Nov 17;2(8151):1073-4. PubMed PMID: 91807.

22: Cartwright RA. Genetic association with bladder cancer. Br Med J. 1979 Sep 29;2(6193):798. PubMed PMID: 519209; PubMed Central PMCID: PMC1596415.

23: Williams DR, Cartwright RA. The esterase D polymorphism in patients with diabetes or carcinoma of the bladder and a matched sample of non-dono. Ann Hum Biol. 1978 May;5(3):281-4. PubMed PMID: 686669.

[1] α-naphthylamine, some of which was contaminated with β-napthylamine, benzidine, dianisidine and o-tolidine

[2] There was a suggestion that the plaintiff’s urologist had invoked his clinical experience in treating men from the factory with bladder cancer, but the courts did not seem to give dispositive weight to this irrelevant argument for causation. Novartis Grimsby Ltd. at 56.

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Daubert Bewigged

September 11th, 2013

Claire McIvor, a senior lecturer, at the Birmingham Law School, has published an interesting U.K. perspective on the use of epidemiologic and statistical evidence in health-outcome litigation. See “Debunking some judicial myths about epidemiology and its relevance to UK tort law,” in 21 Med. Law Rev. (2013), in press.

McIvor argues that British judges have failed to engage with epidemiologic evidence, and have relegated epidemiologic evidence to a status inferior to clinical evidence, even when testifying clinicians have little to offer the fact finder. If the be-wigged judges have done this shame on them, but McIvor suggests that a pre-trial hearing is necessary to address the proper (and improper) range of methodologies and inferences:

“The very fact that methodologically problematic evidence can end up before a trial court is indicative of the need for a pre-trial admissibility test for scientific evidence in UK civil law. Such a test would afford the court an opportunity to evaluate the scientific reliability of any epidemiological evidence that the parties wish to introduce at trial.”

McIvor at 22. In advancing this recommendation, McIvor expands upon a recent Law Commission recommendation for what she describes as “a pre-trial admissibility test for scientific evidence in criminal litigation, similar to that which is used in the USA.” McIvor at 32 (citing Law Commission, Expert Evidence in Criminal Proceedings in England and Wales (Law Comm’n No. 325, 2011)).

This recommendation and discussion, however, are confusing and perhaps confused. The test in the United States is not a pre-trial test, although a party may ask for a determination in advance, either in conjunction with a motion for summary judgment, or to limit the evidentiary display at trial. Nonetheless, objections to expert witness opinion testimony can certainly be made at trial. Indeed, if the pre-trial motion is denied, the moving party may well have to renew its objection at trial in any event.

MacIvor’s recommendation is puzzling for other reasons. First, most civil cases are tried to the bench, and the need to challenge the expert opinion pre-trial is certainly less pressing. Lengthy, methodological challenges are virtually impossible before a jury but they would be made in front of the presiding judge, in any event. Second, having recommended the pre-trial procedure, and the substantive standard for reliability and validity, McIvor proceeds to tell us that it [the Daubert standard] has “proven to be a rather controversial test in practice.” Id. at 32 n.84 (citing no less of an authority than Carl Cranor, Toxic Torts: Science, Law and the Possibility of Justice 62-90 ( 2006)). Cranor is hardly an unbiased, reliable source, but if McIvor accepts his pronouncements, her recommendation is hard to understand. Third, McIvor gives us an example of a class of cases, which at first blush, suggest that judges on the other side of the Atlantic just do not understand science. In McTear v. Imperial Tobacco, [2005] 2 SC 1, the trial judge, Lord Nimmo Smith, ruled in favor of a tobacco company in a lung cancer personal injury case. His ruling was largely based upon a rejection of the epidemiologic evidence, which McIvor suggests is unreasonable, but then tells us that the rejection might have resulted from the plaintiffs’ reliance upon reports without the benefit of an epidemiologist to explain and teach the trial judge about the meaning of the evidence.

Indeed, McIvor tells us that Lord Nimmo Smith complained in his opinion that he had not been:

“‘sufficiently instructed by the expert evidence about this discipline’ to be able to form his own judgment of the evidence. This was not an unreasonable point, at least as regards the issue of individual causation.”

McIvor at 32 (quoting Lord Nimmo Smith). Well, it does suggest that the good Lord may have been a stubborn Scot, who was not going to give any weight to the common wisdom, but rather insist that the plaintiff make his case in court. Even McIvor goes on to characterize the plaintiff’s counsel’s strategy as “unwise, in hindsight.” Id.

Rule 702 is an extremely important part of the law of evidence in federal courts, and in many state courts. The U.K. would do well to adopt it, with allowance for the very different role of judges in civil cases on the other side of the Atlantic.

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Aaron Kesselheim’s Presentation on FDA Regulation of Manufacturer Speech

September 3rd, 2013

On August 5, 2013, Dr. Scott Harkonen filed his petition for a writ of certiorari with the United States Supreme Court. As noted in some previous posts, Dr. Harkonen was acquitted of misbranding, but convicted of wire fraud, for his role in issuing a press release about the results of a clinical trial of interferon gamma 1b, in patients with idiopathic pulmonary fibrosis. (See Multiplicity versus Duplicity – The Harkonen Conviction; The Matrixx Motion in U.S. v. Harkonen; The (Clinical) Trial by Franz Kafka).

Dr. Harkonen’s petition presents two questions:

“1. Whether a conclusion about the meaning of scientific data, one on which scientists may reasonably disagree, satisfies the element of a “false or fraudulent” statement under the wire fraud statute, 18 U.S.C. § 1343?

2. Whether applying 18 U.S.C. § 1343 to scientific conclusions drawn from accurate data violates the First Amendment’s proscription against viewpoint discrimination, or renders the statute, as applied , unconstitutionally vague.”

Both questions are important given that the government has conceded that Dr. Harkonen’s press release accurately presented the raw data and calculated p-values. The crime, if crime it be, lay in Dr. Harkonen’s drawing a causal inference from a subgroup, p = 0.004, which was not prespecified, in a specified secondary endpoint of survival (p = 0.08), when the subgroup was clearly based upon the goals of the trials, and there was other corroborative evidence in the form of two previous trials, clinical practice, and strong mechanistic evidence.

The government argued that NO inferences could be drawn from a trial that “failed” on its primary endpoint. The government’s embrace of this statistical orthodoxy greatly misrepresented scientific practice to the courts below. The only “failed” trial is one that is not conducted.

There are many who would go to great lengths to distort the facts of the Harkonen case in order to demonize the pharmaceutical industry, or to arm the Justice Department with a weapon that can shut down scientific speech about pharmaceutical interventions. The expansion of the Wire Fraud Act, seen in the Harkonen case, to achieve these political goals will not only affect pharmaceutical company scientists, but also government and academic scientists. The standard for falsity, drawn from an out-dated, tendentious, and overly rigid conception of hypothesis testing will apply equally to non-industry scientists in False Claim Act cases. Perhaps in future posts, I can provide some good examples, on condition that any qui tam relators share their bounty with me.

Back in May, Aaron Kesselheim presented (by video) a paper, written with Michelle Mello, of the Harvard School of Public Health, on “The Prospect of Continued FDA Regulation of Manufacturer Promotion in an Era of Expanding Commercial Speech.” Kesselheim went out of his way to misrepresent the facts of the Harkonen case, as part of his brief against off-market promotion.

By way of background, Aaron S. Kesselheim is a physician and a lawyer, and an Assistant Professor of Medicine at Harvard Medical School. He is also a faculty member in the Division of Pharmacoepidemiology and Pharmacoeconomics in the Department of Medicine at Brigham and Women’s Hospital. Given his position and his training in two professions, as well as the extraordinary stakes involved in allowing the government to prosecute scientists for drawing allegedly false conclusions about facts that the government concedes are accurate, Dr. Kesselheim should have exercised much greater care in checking his own assertions more closely.

Dr. Kesselheim focused primarily on the Second Circuit’s recent decision in United States v. Caronia, 703 F.3d 149 (2d Cir. 2012) , which reversed a judgment of conviction for off-label promotion, on First Amendment grounds. About nine minutes into his presentation, Kesselheim turned to alternative strategies for the government to use to squelch off-label promotion. One of his suggestions was to follow the model of the Harkonen prosecution, and to prosecute off-label promotion as false and misleading speech.

In his discussion of his suggested strategy, Kesselheim suggested that Dr. Harkonen had made misleading “conclusory, unsubstantiated claims for efficacy,“ and “without reference to supporting evidence.” It is Kesselheim, however, who seriously mislead his listeners and readers by stating that Dr. Harkonen had made “conclusory, unsubstantiated claims for efficacy.” The Press Release that was the subject of the government’s indictment set out accurately actual count data and calculated p-values. No data were fabricated or falsified. Within the limited space and the informal context of a Press Release, Dr. Harkonen had provided a substantial account of the data from InterMune’s clinical trial, as well as citing a previous, independent clinical trial and its extension, clinical experience, and mechanism research on the action of interferon γ-1b. Unfortunately, it is Kesselheim who is speaking in conclusory sound bites when he ignores the context and content of the actual Press Release at issue.

Kesselheim went on to suggest that Harkonen’s statement was refuted by a “company-sponsored clinical trial showing that the drug was not effective.” This statement is not only false, but shows a flagrant disregard for statistical analysis and the data in the Harkonen case. Kesselheim implies that a clinical trial that fails to show treatment efficacy thereby shows that the treatment was not effective. His statement commits the fundamental error of equating a failure to reject the null hypothesis at a specified level of attained significance with acceptance of the null hypothesis. This reasoning is fallacious and fundamentally flawed.

To be sure, the prespecified secondary survival endpoint in InterMune’s clinical trial did not meet the 0.05 cutoff (it was 0.08), although the per-protocol analysis for this endpoint came up at 0.055, on a preliminary analysis of the data. When the clinical trial was fully analyzed and written up for publication in the New England Journal of Medicine, the treatment-adherent analysis for survival in the entire clinical trial was 0.02, with a statistically significant hazard ratio for survival, favoring the therapy:

“Analysis of the treatment-adherent cohort of patients showed an absolute reduction in the risk of death of 9 percent in the interferon gamma-1b group, as compared with the placebo group, and a relative reduction in the risk of 66 percent (5 percent of 126 patients in the interferon gamma-1b group and 14 percent of 143 patients in the placebo group died, P=0.02). The hazard ratio for death in the interferon gamma-1b group, as compared with the placebo group, was 0.3 (95 percent confidence interval, 0.1 to 0.9).”

Ganesh Raghu, Kevin K. Brown, Williamson Z. Bradford, Karen Starko, Paul W. Noble, David A. Schwartz, and Talmadge E. King, Jr., for the Idiopathic Pulmonary Fibrosis Study Group, “A Placebo-Controlled Trial of Interferon Gamma-1b in Patients with Idiopathic Pulmonary Fibrosis,” 350 New Engl. Med. J. 125, 129-30 (2004).

Dr. Harkonen, in his Press Release, did focus on what seems like an eminently sensible subgroup, within the survival secondary endpoint, of mild- and moderate-cases, which, a priori, were believed to be the patients mostly likely to benefit from the interferon γ-1b therapy. (What was not known before the trial was at what point in disease progression might patients no longer respond with greater survival, and hence the difficulty in setting the boundary between moderate and severe cases.) Kesselheim might argue that the interferon γ-1b clinical trial, standing alone, was inconclusive, but he certainly cannot argue truthfully that the trial showed that the biological product to be ineffective. Clinical trials do not neatly divide the world of possible results into demonstrations of efficacy and demonstrations of inefficacy. Not only does the evidence come in degrees, but there is a range of “inconclusiveness” in between the two extremes. Given his background, training, and experience, Kesselheim certainly should know this, and he should apologize for his inaccurate statements.

Kesselheim might well have stopped there, but he went on to acknowledge that the company-sponsored clinical trial at issue did find, in post-hoc analyses, a non-significant trend of benefit in a subset of patients. Talk of misleading speech! The p-value at issue was 0.004, uncorrected for multiple comparisons, but no one, not Kesslheim, not the government or anyone else, has offered any appropriate adjustment for multiple comparisons that would inflate that 0.004 to over 0.05. Kesselheim has no warrant for branding the subgroup finding “non-significant,” until he shows that the p = 0.004, when appropriately modified (if it can be), exceeds 0.05.

Kesselheim mangles other, less technical facts. He claims that the company saw a ten-fold increase in sales of interferon γ-1b for idiopathic pulmonary fibrosis. No such fact was ever, or could ever, be established in the Harkonen case. Kesselheim claims that Dr. Harkonen admitted, in emails, that he did not really believe that the trial “demonstrated” benefit; no such emails were ever adduced at trial, and this seems to be part of a fictional narrative that Dr. Kesselheim has manufactured. Finally, Kesselheim harrumphs that FDA declined to approve drug. The company never filed a new drug application for the idiopathic pulmonary fibrosis indication; there was no application to reject. Perhaps more important is that the Press Release was issued before InterMune had made any formal submission of data to the FDA, an event that did not take place until the following year.

Kesselheim sighs that the Harkonen prosecution will be a difficult act to follow because it requires a case-by-case showing of falsity, with the necessity of expert testimony, and heavy cognitive demands on lay jurors. How ironic that Kesselheim, a lawyer and a physician, and a Harvard Medical School faculty member, buckled under the cognitive demands of his topic. Indeed, Kesselheim’s confusion is a strong argument for why the Supreme Court should put a stop to the practice of asking jurors to second guess whether a scientist has incorrectly inferred causation from accurately presented facts.

Let’s hope Dr. Harkonen gets a fair hearing in the Supreme Court.

Posted in Scientific Evidence, statistical evidence | Comments Off on Aaron Kesselheim’s Presentation on FDA Regulation of Manufacturer Speech

Trevor Ogden’s Challenge to the Lobby’s Hypocrisy

July 6th, 2013

Trevor Ogden, the editor of the Annals of Occupational Hygiene, addressed sharing of underlying research data in an editorial, a few years ago. See Trevor Ogen, “Data Sharing, Federal Rule of Evidence 702, and the Lions in the Undergrowth,” 53 Ann. Occup. Hyg. 651 (2009). Ogden was responding to attacks on industry-sponsored research and demands that the exposure data from such studies be made available as a condition of publication in the Annals.

Ogden reported that he was sympathetic, to an extent, with the attack on industry bona-fides, but that editorial board discussions raised several issues with data sharing:

“(1) The researcher puts a lot of effort into getting good exposure data and may have plans for their further use; also access to the unpublished data can be an asset in getting further grants.

(2) It takes time and effort to prepare data for publication, and in the short term the people who do this to make their data available are not the ones who benefit by their availability.

(3) There may be problems with confidentiality and liability for the workplaces where the measurements were obtained.

(4) The data may be misused; in particular, they may be reinterpreted by those with a commercial interest in undermining the conclusions drawn by the original researchers.”

Id. at 652.

Had Ogden stopped there, he might have been spared the unceremonious attacks by members of “The Lobby,” but he went further to point out that some of the accusers (David Michaels; McCullogh & Tweedale) were guilty of their own rhetorical excesses.

While acknowledging that industry has taken errant positions or distorted research data on occasions, Ogden thought it was important to note that:

“industry is not always wrong, and campaigners can overlook this because it is easier to identify the paymaster than judge the science.”

* * * *

“It is a mistake if we think that because the industry helped pay for the study and has exploited the findings in its propaganda, the results must necessarily be wrong—life, including science, is not this simple.”

Id. at 653 -54.

Ogden offered, as a scientist would, further alternative explanations for why industry-sponsored scientific research appears to yield results favorable to the sponsor:

“It seems that an industry-sponsored study is much more likely to find results favourable to industry, but this may partly or wholly be because non-industry researchers find it harder to publish negative or inconclusive results. Scientific studies must be judged primarily on the quality of the evidence, not on who pays for them.”

Id. at 654. Ogden might well have opened his mind to the possibility that some government agency and academic scientists may well be biased in favor of finding outcomes that support greater agency regulation and control of occupational and environmental exposures. In any event, Ogden interpreted the situation to require skepticism of all positions, both pro- and anti-industry:

“This is not a very encouraging picture. It looks as if we cannot trust industry, and its critics are not very reliable either.”

Ogden would thus not let any side off the hook when it came to disclosures of potential conflicts of interest:

“Declarations of interest in publications are essential, especially if the authors are likely to be involved in legal testimony. Failure to offer this must be treated very seriously.”

Id. at 655.

Even Ogden’s more modest alternative explanation and his balanced comments provoked shouts of outrage from “the Lobby.” See “The Lobby Lives – Lobbyists Attack IARC for Conducting Scientific Research” (Feb. 19, 2013). Ogden, however, gave them ample space in which to voice their disagreements. See Celester Monforton, Colin Soskolne, John Last, Joseph Ladou, Daniel Teitelbaum , Kathleen Ruff, “Comment on: Ogden T (2009) ‘data sharing, federal rule of evidence 702, and the lions in the undergrowth’,” 54 Ann. Occup. Hyg. 365 (2010); Barry I. Castleman, Fernand Turcotte, Morris Greenberg, “Comment on: Ogden T (2009) ‘Data sharing, Federal Rule of Evidence 702, and the Lions in the Undergrowth’,” 54 Ann. Occup. Hyg. 360 (2010).

The remarkable thing about the Lobby’s letters to the editor is that they scolded industry for conflicts of interests, but failed to reveal their own. Celeste Monforton, for instance, declared her academic affiliations, but overlooked her connection with an anti-Daubert advocacy organization that is funded by left-over common-benefit trust fund money from the silicone gel breast implant litigation. See SKAPP A LOT (April 30, 2010). Monforton and all her co-authors did, however, report their membership in the Rideau Institute on International Affairs, a Canadian “non-profit” organization, established in 2007. They failed, however, to disclose that the Rideau Institute engages in lobbying and advocacy efforts for trade unions and “non-profits.” See Rideau Institute website (“The Rideau Institute is an independent research, advocacy, and consulting group based in Ottawa. It provides research, analysis and commentary on public policy issues to decision makers, opinion leaders and the public.”). Several of Monforton’s co-authors have testified, some frequently, for the litigation industry (plaintiffs) in occupational and environmental exposure cases. Daniel Thau Teitelbaum, for instance, was an early testifier in the silicone breast implant litigation, and was the subject of analysis in General Electric Co. v. Joiner, 522 U.S. 136 (1997).

Barry Castleman’s letter is even more offensive to its own stated principles of extirpating conflicted science. Castleman has been part of the litigation industry’s expert witness army in asbestos cases for over three decades.

Ogden’s statement of the problem was insightful, even if not definitive. His suggestion that “hostile” analysts should be kept from access to underlying data ignores the intense need for this access in areas of science that inform litigation and regulation. As George A. Olah pointed out in his Nobel Prize address, scientists need adversaries to keep them creative, focused, and accurate. Ogden’s call for disclosure of interests, “especially if the authors are likely to be involved in legal testimony,” ignores that litigants on both sides need access to scientific expertise on the issues that drive litigation and regulatory battles. More distressingly, however, Ogden’s journal let his interlocutors slide on their obligation to disclose their deep financial and positional conflicts of interests.

Posted in Conflicts of Interest, Scientific Evidence, Scientific Misconduct | Comments Off on Trevor Ogden’s Challenge to the Lobby’s Hypocrisy

Federal Rule of Evidence 106 Applied to Statistical Evidence

June 18th, 2013

Watching your expert witness harassed by an unfair crossexamination, without protection from the trial judge, is one of the most frustrating, annoying, and enraging events in trial. Not so long ago, I had the experience of having a lawyer put a chart together during his crossexamination of an expert witness. The crossexaminer took the upper bound of each confidence interval, and asked “Based upon this study, the true relative risk could be as high as X?” When the witness, naturally and properly pointed out that the study data were also compatible with a relative risk as low as Y, the lower bound of the confidence interval, the crossexaminer whined that the witness was not being responsive, with the trial court’s chiming in to curb the expert’s reasonable desire to have a complete, correct answer.

Watching events such as this crossexamination has led me to believe that there really should be a rule of completeness for statistical evidence. If sampling is random and unbiased, a point estimate may be the best estimate of the true value of a mean or a proportion, but that estimate may be rather crummy if the random error is large. Presenting the sample statistic without some idea of the standard error seems wrong, but is there a remedy?

Statistical evidence did not play much of a role in the development of common law evidence, but the law is concerned with the sort of contextual accuracy that was being abused by the crossexamination of the expert witness, above. The Federal Rules provide for completeness in at least two contexts. Federal Rule of Evidence 106 provides:

“Remainder of or Related Writings or Recorded Statements

If a party introduces all or part of a writing or recorded statement, an adverse party may require the introduction, at that time, of any other part — or any other writing or recorded statement — that in fairness ought to be considered at the same time.”

A similar rule governs depositions presented in court. Federal Rule of Civil Procedure 32(a)(4).

As the Advisory Committee notes to Rule 106 point out, Rule 106 is based upon two basic considerations:

“The first is the misleading impression created by taking matters out of context. The second is the inadequacy of repair work when delayed to a point later in the trial. … The rule does not in any way circumscribe the right of the adversary to develop the matter on cross-examination or as part of his own case.”

Rule 106, Advisory Committee Notes (internal citations omitted).

When “in fairness” should an omitted portion be considered contemporaneously? Here is how the Seventh Circuit put the matter in the more mundane context of a writing:

“To determine whether a disputed portion is necessary, the district court considers whether

(1) it explains the admitted evidence,

(2) places the admitted evidence in context,

(3) avoids misleading the jury, and

(4) insures fair and impartial understanding of the evidence.”

United States v. Velasco, 953 F.2d 1467, 1475 (7th Cir.1992).

Presentation of a point estimate should be accompanied by a measure of its variability; “[w]henever possible, an estimate should be accompanied by its standard error.” Reference Manual on Scientific Evidence at 117-18 (2d ed. 2000). Similarly, trial courts should be vigilant against permitting a party to use the upper or the lower bound of a confidence interval to paint a misleading picture of “what the evidence shows.”

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Sympathy for the Diablo — Peppermint Barry vs Spicy Seafood Pasta

June 12th, 2013

Barry S. Levy is a physician, author, performer, and political activist. Dr. Levy is a past president of the American Public Health Association, which conferred upon him its oldest and most prestigious award, the Sedgwick Memorial Medal, in 2005, for his outstanding achievements in public health.

Levy has been received other, less favorable notice from trial and appellate judges. For instance, one federal judge found Levy engaged in a dubious enterprise to manufacture silicosis claims in Mississippi. In re Silica Products Liability Litigation, 398 F. Supp. 2d 563, 611-16, 622 & n.100 (S.D. Texas 2005) (expressing particular disappointment with Dr. Barry Levy, who although not the worst offender of a bad lot of physicians, betrayed his “sterling credentials” in a questionable enterprise to manufacture diagnoses of silicosis for litigation). See also Schachtman, Silica Litigation: Screening, Scheming & Suing; Washington Legal Foundation Critical Legal Issues Working Paper Series No. 135 (Dec. 2005) (exploring the ethical and legal implications of the entrepreneurial litigation in which Levy and others were involved).

Unfortunately, In re Silica was not an isolated case. See, e.g., Lofgren v. Motorola, Inc., 1998 WL 299925, No. CV 93-05521 (Ariz. Super. Ct., Maricopa Cty. June 1, 1998); Harman v. Lipari, N.J. L. Div. GLO-L-1375-95, Order of Nov. 3, 2000 (Tomasello, J.) (barring the use of Barry Levy in class action for medical monitoring damages); Castellow v. Chevron USA, 97 F.Supp. 2d 780, 793-95 (S.D. Tex. 2000); Knight v. Kirby Inland Marine Inc., 482 F.3d 347 (5th Cir. 2007); Watts v. Radiator Specialty Co., 990 So. 2d 143 (Miss. 2008); Aurand v. Norfolk So. Ry., 802 F.Supp.2d 950 (2011).

Now, once again, right here in River City, Dr. Levy has stepped out of bounds, and has been stripped of his mantle of testifying expert witness. Mallozzi v. Ecosmart Technologies, Inc., 2013 WL 2415677, No. 11-CV-2884 (SJF)(ARL) (E.D.N.Y. May 31, 2013).

Over the course of a few minutes, plaintiff Velio Mallozi applied a “couple of ounces” of EcoSmart Organic Home Pest Control product to the foundation of his home, and a few squirts inside. The product used, EcoSmart, contains plant oils, including one percent peppermint oil. Id. at *1. Mallozi did not experience any acute ill effects from his organic pest control efforts, and later went to dinner at an [unidentified] Italian restaurant, where he enjoyed a meal of “spaghetti with seafood.” Id. at *10. Perhaps seafood diablo, but Judge Feuerstein doesn’t say.

After the seafood spaghetti meal, Mallozi experienced a serious bout of laryngopharyngeal reflux (LPR). With sympathy for the diablo, Mallozi sued only EcoSmart, on the claim that his inhaling some spray, with its 1% peppermint oil, caused his LPR.

The Mallozis sought out B.S. Levy to support the claimed relationship. Levy did not disappoint. He rendered a report that asserted that the few minutes of inhaling minor amounts of peppermint oil causes relaxation of the lower esophogeal sphincter, and consequently LPR. Id. at *5. Levy relied upon four articles to support this claim, but Judge Feuerstein refused to accept the claim of support, at face value. Her Honor reviewed each study, only to find that the exposures that were associated with relaxation of G.I. smooth muscle, for a short period of about 20 minutes, were trials of ingested peppermint oil, at significantly greater doses, over lengthy periods of observation. Id. at *6. The studies individually and collectively did not support Levy’s opinion.

One of the papers on Levy’s reliance list was a case report of a patient that suffered burns in her mouth from ingestion of pure peppermint oil. The court found that this case report, involving large doses of pure peppermint oil, with an outcome different from claimed by Mallozi, was irrelevant. Id. Even if it were construed to offer some support, the anecdotal nature of the case report, lacking controls, renders the report an unreliable basis for a causal conclusion. Id.

The trial court found that B.S. Levy’s analysis ignored the crucial roles of dose, duration, route of exposure, and the nature of plaintiff’s condition, LPR. Id. at *8. The court held that Levy’s opinion did not satisfy the requirements of Rule 702. The plaintiffs failed to show that Levy’s opinion was supported sufficiently by facts or data, and they failed to show that his opinion was the product of applying reliable methods and principles. Id.

Judge Feuerstein, having found that Levy’s opinion on general causation between EcoSmart and LPR was bereft of validity, could have stopped without addressing specific causation. Such an approach would have had the virtue of judicial economy, but would have left out some delicious facts. Levy purportedly used some sort of differential etiology to infer the cause of plaintiff’s LPR, but he omitted meaningful consideration of plaintiff’s having had a history of severe severe gastroesophageal reflux disease (GERD), which predated his bout of LPR. Indeed, plaintiff’s GERD had been so severe that he had been previously hospitalized for GERD after ingesting coffee and donuts. Judge Feuerstein found Levy’s iterative disjunctive syllogism invalid for having failed to address the prior history of GERD, and the intervening role of the pasta and seafood dinner, in bringing on the LPR. Id. at *10-11.

The Material Safety Data Sheet Ploy

Judge Feuerstein also demonstrated a careful understanding of the meaning and role of the Material Data Safety Sheet (MSDS). EcoSmart’s MSDS contained a warning that some sensitive persons may experience dizziness or irritation of their nasal passages, and that ingestion may cause GI irritation. Id. at *13. Dr. Levy had embraced this MSDS language as an “admission,” but he did not analyze the sources of information or their validity. The MSDS warning, as required by law, addresses the potential hazard of the ingredient, peppermint oil, irrespective of dose, concentration, or route of administration. Id., citing Moore v. Ashland Chem. Inc., 151 F.3d 269, 278 (5th Cir.1998); Turner v. Iowa Fire Equip. Co., 229 F.3d 1202, 1209 (8th Cir.2000); Ingram v. Solkatronic Chem., Inc., No. 04–CV–0287, 2005 WL 3544244, at *6 (N.D.Okla. Dec. 28, 2005)).

The Treating Physician Echo

Apparently one of Mr. Mallozzi’s treating physicians joined the fray with echoes of Levy’s opinion. Judge Feuerstein recognized that treating physicians are subject to the requirements of Rule 702, and that a me-too opinion deserved the me-too result. Id. at *13, citing Davids v. Novartis Pharm. Corp., 857 F.Supp. 2d 267, 280 (E.D.N.Y. 2012).

Pasta and Peppermints

Bad sense, innocence, cripplin’ my mind.
Old medical records I just can’t find.
Too much Cajun spice, and I forgot about GERD.
Incense and peppermints, haven’t you heard?
But who cares, it’s just litigation.
Lots to win, but nothing to lose.

Incense and peppermints, meaningless claims.
Turn on, drop in, toxins are all the same

Throw your pride to the side; it’s what you must do.

Daubert is politics; 702.
A yardstick for lunatics, your point of view.
The court cares what games you choose.
You have lots to win, but nothing to lose

(adapted from, and with apologies to, Strawberry Alarm Clock)

Posted in Causation, Expert Witnesses, Rule 702, Scientific Evidence | Comments Off on Sympathy for the Diablo — Peppermint Barry vs Spicy Seafood Pasta