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.
