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-Oct-97 04:03P 0181 642 2135 "I5 vRvjlonmental tobi!.C,_C,o ~moke • n evaluation of th(; evidence" Comments on the paper bv M R I.aw. J K Morris and N J Wald in the British Medical Journal (1997. 315.973-980) The claims Law, Morris and Wald claim that "breathing other people's smoke is an important and avoidable cause of ischaemic heart disease [IHD], increasing a person's risk by a quarter." This conclusion is based on a sequence of observations and analyses. First, based on a meta-analysis of 19 epidemiological studies they estimated that. among never smokers, exposure to environmental tobacco smoke [ETS]. as indexed by spousal smoking, is associated with a relative risk of IHD of 1.30 (95% confidence interval [CI] 1.22 to 1.38). Second, based on extrapolation of results for smokers from five US and UK studies of smoking and heart disease, the.,,, estimated that smoking one cigarette a day is associated with a risk of IHD. relative to that in nonsmokers, of 1.39 (!. 18 to 1.64) Third, for both the smoking of one cigarette a day'and for E'rS exposure, they argue that the estimated excess risks (39% and 30% respectively) are much higher than would be expected (4% and 0.8% respectively) based on simple linear extrapolation from the observed excess risk of 78% in smokers of 20 cigarettes per day. Fourth. they estimate that confounding by differences in diet associated with ETS cxposure only explains a rclativc risk of 1.06, a bias insufficient to explain the relative risk of 1.30 estimated from the meta-analysis. The bias due to confounding by diet was estimated by two completely different techniques:

04:03P 018! 642 2135 (i) (ii) 2 "direct estimate" :- based on the magnitude of the association of diet with 1HD and on the magnitude of the difference in diet between nonsmokers ~vho live and do not live with smokers; "indirect estimate" :- based on the excess risk of IHD observed in long term ex- smokers. Fifth, based on a UK epidemiological study relating platelet aggregation to risk of subsequent IHD, and on various short term studies relating smoking and ETS exposure to platelet aggregation, they estimate that ETS exposure is likely to increase risk of IHD by 34%, due to its effects on platelet aggrega.tion. They regard the increase in platelet aggregation as providing a plausible and quantitatively consistent mechanism for the unexpectedly high risks associated with ETS and low dose cigarette smoking. P.03

.30 -~).c t - 97 04:03P 0181 642 2135 P.04 3 Weaknesses of the claim~ The evidence presented by Law, Morris a~d Wald is seriously misleading. As is made clear in section 4, where our comments are elaborated in more detail, major weaknesses of the paper are as follows: E~clusion from the recta-analysis of data from the American Cancer Society [ACS] Cancer Prevention Study-I [CPS-I] is totally unjustified, and seriously distorts the estimated association of ETS with spousal smoking. There is also no good reason to exclude data from the National Mortality Followback Survey [IxlMFS] (see section 4. !. ! ). The fact that the combined epidemiological evidence shows no significant association between ETS and workplace exposure never emerges, partly because Law, Morris and Wald restrict detailed attention to spousal smoking as the index of ETS exposure and partly because they misleadingly cite an out-of-date and erroneous meta-analysis by Wells (1995) (section 4.2). Bias due to misclassification of active smoking status is incorrectly assumed to be negligible. Evidence of high heart disease rates in misclassified smokers is ignored (section 4.3). Both the "direct" and "indirect" estimates of confounding bias are open to question. Confotmding could make a major contribution to the observed association (section 4.4). Publication bias is inadequately considered. Not only is there direct cvidcncc that major data sets have v,aongly been excluded from the recta-analysis, but the analysis of publication bias conducted by Laxv, Morris and Wald is inappropriate. merely attempting to refute the proposition that the whole ofthe association may result from this source of bias (section 4.5).

30~0ct-97 04:03P 018l 642 213b 10. 4 Other potential sources of bias are not considered at all (scction 4.61. The claim that the relative risks from the studies of spousal smoking and heart disease are homogeneous is unjustified; smaller, weaker studies show substantially higher risks (section 4.7). Estimates of risk from smoking one cigarette per day or from ETS exposure obtained by extrapolation from evidence in active smokers are subject to huge uncertainty (section 4.8). The theory, proposed by Law, Morris and WaId, ~vith the excess risk resulting from smoking of one cigarette a day only slightly greater than that from ETS exposure, suggests that, within nonsmokers, there would be little or no discernible dose-response with level of ETS exposure. Ho~vever Law, Morris and Wald do not even consider the evidence on dose-response from the spousal smoking studies. Although these results arc heterogeneous, a number report a statistically significant trend, in apparent conflict with the theory (section 4.9). There are considerable difficulties in interpreting the evidence on platelet aggregation as relevant to the possible effect of ETS on heart disease (section 4.10).

' 30-8ct-97 04:04P 0181 642 2135 P.06 An alternative view of the evi_d_e_I!_e~ Based on the evidence available it is possible to arrive at an alternative interpretation very different from that put forward by Law, Morris and Wald. Exposure to ETS is very much less than is exposure to tobacco smoke. Based on the evidence for active smoking it is not possible to infer with confidence that low exposures are associated with any excess risk of IHD, let alone with an excess risk of 30% or so. When all the epidemiologieal evidence relating ETS to heart disease is considered the magnitude of any association is clearly substantially less than the relative risk estimate of 1.30 cited by Law, Morris ~md Wald. It is quite plausible that the various sources of bias and confounding, when taken properly into account, could explain the whole of the observed association. It is also possible that a true excess risk may exist, much smaller than the increase of a quarter claimed by Law, Morris and Wald.

~0-{)cL-97 04:04P 0|81 4.1 4.1.1 Detailed comments 6 Data and studies included in recta-analysis • Law, Morris and Wald present, in their Figure 1, and use in their morn-analysis, relative risk estimates for spousal smoking adjusted for age and sex from 19 epidemiological studies. Elsewhere, in a paper made available at the 10th World Conference on Tobacco or Health, held in Beijing, Lee (1997) presents results of an independent recta-analysis based on data published by the end of 1996. It is useful to compare the data and studies included in the v, vo recta-analyses, especially since they have a very great effect on the conclusions. Lee (1997) considers data from 23 studies, covering all the 19 studies considered by Law, Morris and Wald, and four additional studies. For two studies (Palmer, 1988; Marmino, 1995) only relative risk estimates (respectively 1.20 and 1.12) and not confidence limits were presented so the data could not usefully be included in recta- analyses. The other two studies are the ACS CPS-I study (LeVois and Layard, 1995) and the NMFS study (Layard, 1995). deliberately excluded by Law, Morris and Wald because Layard and LeVois were consultants to the tobacco industry, because the reported results were inconsistent with those of the other studies considered by Law. Morris and Wald and because the analysis by Layard and LeVois ofdata from the ACS CPS-II study was considered inconsistent with the results of a later analysis commissioned by the American Cancer Society (Steenland et al, 1996). The 19 studies included by Law, Morris and Wald involved a total of 6600 [HD events among never smokers. The NMFS study involved 1389 IHD deaths while the ACS CPS-I! study involved 14,891. Inasmuch as the NMFS study data are publicly available, it was clearly open to Law, Morris and Waid to access the data and conduct their own analyses if they did not betieve the results reported by Layard (1995). Failure to do so limits the extent to which

3~±0ct-97 0¢:04P 0181 64~ 2135 P.08 4.1.2. 7 the data considered by Law, Morris and Wald can be regarded as representative. However, omission of the study is clearly less important than is omission of the huge ACS CPS-I study. Issues relatin8 to this are discussed in more detail in the section that follows. Failure to include data from the ACS CPS-! study The ACS CPS-I study involved more than one million men and women in 25 US states in 1959-60 follosved up until 1972. Its results relating to smoking and health are widely cited and indeed Law', Morris and Wald cite some of its results for active smoking in their paper. Subjects were asked about their own smoking habits but not about smoking by their spouse or about ETS exposure. However, as is also the case for other well-known ETS epidemiological studies (e.g. Hirayama, 1981). inte~ie',vs were conducted on all adults in the household so it was possible to identify spousal smoking status from the responses of the spouse. In 1981 ,the ACS reported results relating to spousal smoking and lung cancer from CPS-I (Garfinkcl, 1981 ), based on a total of 153 lung cancer cases in never smoking xvomen. Since IHD in a never smoker is very. much commoner than is lung cancer in a never smoker, it has been evident for many years that the study has the potential to provide valuable data relating spousal smoking to risk of IHD (and other diseases also). Lee has, on a number of occasions (Lee, 1990. 1991a, 1991b, 1992a, 1992b), made it clear that the failure of the ACS to provide results from CPS-I may have caused severe bias to the published literature on ETS and IHD. He notes (Lee, 1992b) that in about 1987 he visited the ACS in New York and had been told by Gaxfinkel that they had examined the data on spousal smoking and IHD from CPS-I but had found no relationship. At that time Garfinkel had said they were awaiting results from CPS-II before publishing.

30-0ct-97 04:05P 0181 64? Z [35 ~*.u~ To this date, the ACS have never published data from CPS-I though they have published data from CPS-II. In a recently published correspondence in Circulation (LeVois, 1997; Steenland et al, 1997; Glantz and Parmley, 1997), arising c~ut of the Steenland et al (1996) paper, the ACS argue that they did not analyse ETS exposure among never smokers in CPS-I because there were no direct questions on ETS exposure and therefore no information on ETS exposure outside the home, so making it difl"tcult to identify a truly non-exposed comparison group. While clearly, in an ideal world, one would like to have data on all sources of ETS exposure, this hardly .seems a reason for non-publication of the results. After all, much of the published literature relates only to spousal smoking as an index of exposure, and Law, Morris and Wald have restricted attention to this index. Law, Morris and Wald do not actually cite inadequacy of the ETS data from CPS- I as a reason for not including the results of LeVois and Layard (1995) in their recta- analysis. Their reasons relate more to suspicions about the validity of the analyses reported by LeVois and Layard. There are two major points to be made here. First, if Law, Morris and Wald had such suspicions, then surely it was absolutely imperative for them to carry out their own analyses ofthe data. With the study providing information on about twice as many cases of IHD as the rest of the published evidence put together, there is no way that its results should be excluded from any self-respecting overview of the data. Second, there seems no great reason to express doubts regarding the validity of the analyses of LeVois and Layard (1995). For both CPS-I and CPS-II they presented results relating risk ofll ID among never smokers to the smoking habits reported by the spouse as follows:

"03-NOU-1997 15:30 GRLLRHER CORPORRTE RFFRS 01932832532 9 Sr~tise smokinff habits Men Women Men Women ~ever smoked 1.00 1.00 i.00 1.00 F.~-smoker 0.95(0.83-1.09) 0.99(0.93-1.05) 0.81(0.70.0.93) 0.99(0.$6. I. Curren| l-I 9 ¢igr,/day 0.99(0.$9-1.09) 1.04(0.97-1.12) l.~]6(l.10-1.65) 1.14(0.86-l.51 } Current 20-39 rigs/day 0.98(0.85-I.13) 1.06(0.95-1.1 $) 1.26(I,00-1.58) 0,98(0.75-1.29) Current ~)+ cigs/day 0.72(0.4 l- 1.2.8) 0.95(0.78- I. ! 5) !, 13(0.6 !-2. I 1 ) 1.27(0.$0-2.0 I • Pipe/cigar only ! •06(0.99. I.I 4) 0.98(0.79- i.20) Ever amoked 0.97(0.90.1.05) 1.03(0.98-1.08) 0.97(0.87-1.08) Note: Relative risks ~nd Cls are adjusted for age ~nd race. For CPS-ff the most comparable results reported by Steenland et ol (i 996) arc as follows: Spouse smoking habits Men Women Never smoked 1.00 1.00 Ex-smoker 0.96(0.$3- I. 1 I) 1.00(0.88- !. ! 3) Current. ! - 19 eig~,'d~y 1.330.09-1.6 I) I. 15(0.90. I .d 8) Current 20 cigrddgy I.I 7(0.92-I .48) 1,07(0.83- 1.40) Current 20+ (2'1-39) cigs/day !.09(0.77-I.$3) 0.99(0.67-1.47) Current 40+ elf, s/day ! .04(0.67- i .6 l) Current any 1.22(i.07- i.40) I. ! 01~0.96-1.27) Note: Relative fisk~ end Cls tre adjured for ~ge, self-reported hislory of heart disease, hypertension. diabc~s end at~u'llls, body mass index, education, use of aspirin, dbretics, aestrogen and alcohol, .. exercise and employment ~tus. Comparing the LeVois and Layard (1995) CPS4I results with those reported by Steenland e~' m~ 0996) it can bc sccn that, despite differences in adjustment factors, subject exclusion criteria and groupings of amount smoked, there are considerable similarities in the reported findings. Thus: • (i) they both show no evidence of an increase in risk for ex-smoking spouses, though LcVois and Layard show rather lower risks for men, P.02/26

"O~-HOU-1997 15:30 GALLAHER CORPORA%E AFFRS 81932832532 (iii) I0 they both show no evidence of a dose-relationship with amount smoked currently , by, the spouse, and they both show some indication of an increased ri~ for current smoking spouses ovcrall, similar except far women married to heavy smokcrs where LeVois and Layard show rather higher risks. (ii) ' A difference has arisen in the overall interpretation because LeVois ,-rod Layard concentrated on the st,,emery relative risk for ~,..~~ whereas Stccnland el al concentrated on the summary reladvc risk for s~_u~ current smoker. In considering d~is choice it should be noted that: (i) many of the studies considered by Law, Morris and Weld have only presented daia for spouse ever smoked, Jn rp/OspeCtiv¢ $~dJes many spouses who were current smokers at the time of interview will have become ex-smokers before the IHD event subse4uently occurred, and (iii) among those studies which present data for both spouse ever smoked ~d for spousc era'rent smoker, Steerdand et a! (I996) is the only one where the distinction mateti~lly affects the relative risk estimate. W~ile it might bc argued that LeVois and LayaM should also have presented o~erall relative risk estimates for spouse current smoker, one can hardly ~gue that their analYses are flawed. The key point to notc is that LeVois and Layard's analysis for ~7,E,5-_[ (see t~ble above) does not suggest any increase at all in IHD risk for men married to current smokcts (Lee, 1997 estimated 0,98, 95% CI 0.91 to 1.06) and only the most modest increase, for women married to current smokers (I .04, 0.99 to 1.09). P.03/26 It is clear that omission of CP$-I was unjustified and will cause considm, able bias.