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In response to Mr. Lee’s comment1 which follows previous responses2,3
and my paper4, I offer further
explanation to resolve an apparent misunderstanding of the validity and
reliability of cotinine/creatinine ratio (CCR) measurement and his mishandling
of the formula of misclassification. I also express concerns about the lack of
scientific integrity in his reporting5 of the Japanese spousal study,
including his authorship.
As I demonstrated4, all indices of nicotine exposure (ambient
room,personal sampler monitors, and salivary
were well correlated but correlated poorly with CCR, raising doubts about the
validity of the CCR measurement. Yet
Lee maintains that CCR measurement in this study was the gold standard for
distinguishing true smokers from falsely reporting smokers.
There are several possibilities about why the CCR
measurement may have been invalid and unreliable in this study. In 1991 when I
sent the urine samples to the RJR laboratory (where the measurement was
performed), I was informed that all the dry ice sent with the sample had
sublimated before it reached the laboratory. This suggests that the sample was
not maintained at low temperature before analysis. Cotinine measurement is
temperature sensitive and measurement after the sample is exposed to high
temperature can make the measurement inaccurate6.
As I calculated4, the misclassification
and reverse misclassification were equally high suggesting inappropriateness of
the CCR measurements as the gold standard. Lee’s
neglect of reverse
him to claim an inflated false negative rate of smoking.Lee continues to justify his
misclassification formula by referring to his previous use of the formula.
However, this formula is dependent
on the prevalence of smoking among the study population and thereby artificially
inflates the misclassification rate
of populations with low smoking
prevalence. By way of illustration, consider two hypothetical populations of
1000 people each with smoking rates of 10% (A) and 30% (B).
Suppose that, due to the inaccurate CCR measurement, just 3% of true
smokers are classified as non-smokers by erroneously low CCRand
3% of true non-smokers are classified as smokers by erroneously high CCR
(for the sake of simplification, I assume no false reports by the subjects). We
will get the following results.
A: If 10% smoke
If 30% smoke
can be seen, Lee’s formula for misclassification is dependent on the
prevalence of smoking. With only a
slight (3%) inaccuracy in CCR measurement, he can thereby easily get more than
three times higher (0.21
vs.0.06) misclassification in a population with lower smoking prevalence, such as with Asian women.
After a long discussion between Proctor and me, Proctor finally
understood and accepted my point on the misclassification formula7.
Our final draft of the misclassification paper8, which Proctor sent
to me on November 9, 1992 with my name as a sole author, clearly mentioned the
high proportion of misclassification in both sides (self-reported non-smoking
subjects with high CCR and self-reported smokers with low CCR).
insists that reverse misclassification is relatively unimportant in his
abundant mathematical publications. However, I note that he seems to have
realized his mistake of using 28/106 as the misclassification rate of
self-reported smokers in his original study5 , having quietly
switched to 28/98 for this rate1 after I pointed out his confusion.
Despite his claim that reverse misclassification is implausible, it was observed
as a fact.
states that as
far as he is aware the
data never belonged to Yano. He should be aware that I developed the
questionnaire, and selected the study areas and subjects. I supervised the
survey at the study area (Shizuoka), erroneously referred to in Lee’s paper as Shizoka5. I planned and ordered the
data input, performed the data analysis and sent the disk to Proctor. On
learning from the experience of possible sample damage (from dry ice
sublimation) by the commercial shipment at the first phase study in 1991, I even
transported the second phase samples myself to the RJR laboratory, Winston
Salem, NC where CCR was measured. I discussed the scientific content of the
study with Proctor many times and he accepted my points7 and revised
the draft many times, always with my name as the author, and never with Lee’s.
As can be seen in the final draft8, Proctor and I reached a certain
agreement on the misclassification formula and the importance of the reverse
Lee never participated in the actual survey it may be that he was unaware of
details of the research such as the integrity of the sample which may have
seriously affected the interpretation of results. Nor did he participate in the
discussion which led Proctor and I to a deeper understanding of the analysis7.
Despite this, still Lee claims that because he proposed the research project, he
has a right to sole authorship
regardless of who actually conducted the research. This is a unique idea that
few scientists would accept.
Lee states: Had I not published the paper it seems that the findings
would never have appeared in the public domain at all.
Did Yano also have sole rights to suppress the findings? Again, I
remind Lee that Proctor and I
agreed that the results did not indicate high misclassification in self-report
non-smokers but some failure in the study.7, 8 What both Proctor and
I prepared for publication, although Proctor ceased to contact me before we
could reach a final agreement, was totally different from what Lee eventually
published5. I consider that a description of a failed study
involving the inaccurate measurement of CCR was undeserving of publication.
Moreover, as a scientist committed to truth, I have a responsibility to be
critical of a report with erroneous interpretations based on invalid
Lee PN. Response to
and S Chapman [Commentary]. Tob Control, 2005; 9 Sep 2005 http://www.tobaccocontrol.com/cgi/eletters/14/4/234#410
2. Yano E. Response
to P N Lee [Commentary]. Tob
Lee PN. Japanese spousal
study: a response to Professor Yano's claims [Commentary].
Tob Control 2005;14:233-4.
Yano E. Japanese spousal smoking study
revisited: how a tobacco industry funded paper reached erroneous conclusions. Tob
Lee PN. "Marriage to a smoker" may
not be a valid marker of exposure in studies relating
tobacco smoke to risk of lung cancer in Japanese non-smoking women.
Int Arch Occup Environ Health 1995;67:287-94.
RL, Ramos JM Jr, Jacob PM 3rd. Increasing urinary cotinine concentrations at
elevated temperatures: the role of conjugated metabolites. J Pharm Biomed
CJ. Fax to Dr E. Yano,
, October 26 1992.
CJ. Fax to Dr E. Yano,
re: A comparison of lifestyle factors for Japanese non smoking women married to
smokers with those married to non-smokers, November 9 1992. http://tobacco.health.usyd.edu.au/tds/details.jsp?document_id=CB_MIS_00006B
Response to E Yano and S Chapman
P N Lee
Professor Eiji Yano raises a number of issues in his letter(1) which
responded to my commentary(2) on his article(3) about the Japanese spousal
study, as does Chapman in his editorial(4). Here I reply to the main
INTERPRETATION OF THE DATA
Studies of environmental tobacco smoke (ETS) exposure and lung cancer
commonly identify a...
Studies of environmental tobacco smoke (ETS) exposure and lung cancer
commonly identify a group of self-reported non-smoking women and then
compare risk according to the smoking habits of the husband. If some true
smokers are erroneously included among the female subjects, an apparent
relationship of spousal smoking with lung cancer may be seen even when no
true effect of ETS exists. This has been mathematically demonstrated
(e.g.5), with attempts to correct for it made by major independent
authoritative reviews of the evidence on passive smoking and lung
cancer.(6-8) The magnitude of the bias depends (among other things) on
the extent to which women who smoke are misclassified as non-smokers. It
can also be shown mathematically(5) that a given rate of misclassification
of smokers as non-smokers is a much more important cause of bias than is
the same rate of the reverse misclassification, of non-smokers as smokers.
Since such reverse misclassification is also implausible, adult women
having little reason to claim erroneously to be smokers, the major
reviews(6-8) have all ignored its minor effects.
Given that in the Japanese spousal study (using a urinary
cotinine/creatinine ratio, CCR, above 100 ng/mg as an index of true
smoking), the reverse misclassification rate (8/298 = 2.7%) was anyway
much lower than the misclassification rate itself (28/98 = 28.6%), it
becomes abundantly clear that reverse misclassification is not relevant to
the passive smoking/lung cancer issue. It is difficult to understand why
Yano places such emphasis on it.
Yano(1) states that I am "confused with the calculation formula" and
that my "definition of misclassification was obtained by dividing those
with >100 ng/mg CCR (n = 28) by self-reported non-smokers (n = 318)."
It appears that Yano himself is confused. I had previously made it
clear(2) that the denominator should not be 318, but 98, the number of
women with a CCR value indicative of smoking (or perhaps 106, if one also
includes those women who claimed to smoke but had a CCR <100 ng/ml).
The misclassification rate calculation is clearly based on CCR
>100 ng/mg validly indicating smoking. Such an assumption is widely
used(9), though may be subject to some error, and was the best technique
available at the time. Most smokers admit to smoking, so that self-report
has some validity as an indicator of true smoking status, but this does
not help us estimate the magnitude of the misclassification bias. The
observed lack of correlation in the Japanese spousal study between CCR in
non-smokers (with CCR <100 ng/mg) and other indices of ETS exposure
suggests that inaccuracy in CCR measurement at low levels may be
important. However, such inaccuracy may not be relevant to the
misclassification rate calculation, which merely attempts to use CCR to
distinguish smokers from non-smokers. Over half the self-reported non-
smokers with values over 100 ng/mg actually had values of 1000 ng/mg, and
it would be very surprising indeed if errors in CCR measurement were so
huge that these women were really non-smokers.
Though I would be happy to see results of further studies using up-to
-date state-of-the-art chemical methods to detect nicotine metabolites in
self-reported non-smokers, the conclusion I reached in 1995 that
misclassification rates are much higher in Japanese than in Western
populations(10) seems to be correct. I note that the existence of high
misclassification rates in Asian women has in fact been independently
RIGHTS TO PUBLICATION OF THE FINDINGS
Yano states(1) that I used his data without his consent. As far as I
am aware, the data never belonged to Yano. The study had been funded by
the industry who had carried out the cotinine analyses (blind of self-
reported smoking status). I had originally proposed that the study be
done, following conduct of a similar study in England, which the industry
supported at my request, and which I reported the results of.(12) The
original intention had been for Yano to be a major author, but problems
arose because his interpretation of the findings differed materially from
mine, due to his misunderstanding of the complexities of
misclassification. Discussions took place between Yano and Proctor, who
played an important role in planning and organisation of the study on
behalf of the tobacco companies who funded it, and I was told that these
discussions led to Yano deciding not to be an author, and to his
understanding that the work would be published by others.
I had assumed that Proctor would keep Yano informed about the status
of the publication and was surprised Yano did not find out about the
paper, published in 1995, until some 7 or 8 years later. Clearly, one of
us should have kept him informed, and for this I apologise. In his
original article,(3) Yano states that "at no stage in my interactions with
Proctor was Lee's name or role ever mentioned." This is surprising
inasmuch as the study proposal stated that I would assist in reviewing the
study design and in interpreting the data. Was Yano really unaware of the
previous literature on misclassification of smoking, in which I figured
prominently (see 2) when conducting a study, a major aim of which
concerned the determination of misclassification rates?
Chapman(4) considers that "it is hard to imagine a more flagrant example
of attempted ghost authorship". It is difficult to see why Chapman sees
the publication as ghost authorship at all, when I proposed the study,
helped in its design and then published it. The study was a joint
enterprise, as I saw it, and it is perfectly normal for some of the
scientists involved in a study to write a draft for others to agree to.
It would clearly have been better had a version acceptable to all, with
Yano in the author list, been published. However, Yano's failure to
understand the mathematics of misclassification made this impossible.
There was no agreement I am aware of that Yano had sole rights to
authorship. Had I not published the paper(10) it seems that the findings
would never have appeared in the public domain at all. Did Yano also
have sole rights to suppress the findings?
At the end of the day it is interesting that, though the evidence of high
misclassification rates in Japanese women has been independently
confirmed,(11) the relevance of this to the ETS/lung cancer relationship
has been ignored in recent major reviews of ETS and lung cancer
(e.g.8,13). I have demonstrated the major biasing effect of this finding
in detail elsewhere(14).
1. Yano E. Response to P N Lee [Commentary]. Tob Control
2. Lee PN. Japanese spousal study: a response to Professor Yano's
claims [Commentary]. Tob Control 2005;14:233-4.
3. Yano E. Japanese spousal smoking study revisited: how a tobacco
industry funded paper reached erroneous conclusions. Tob Control
4. Chapman S. Research from tobacco industry affiliated authors:
need for particular vigilance [Editorial]. Tob Control 2005;14:217-9.
5. Lee PN, Forey BA. Misclassification of smoking habits as a
source of bias in the study of environmental tobacco smoke and lung
cancer. Stat Med 1996;15:581-605.
6. Committee on Passive Smoking, Board on Environmental Studies and
Toxicology, National Research Council. Environmental tobacco smoke.
Measuring exposures and assessing health effects. Washington D.C.:
National Academy Press; 1986.
7. National Cancer Institute. Shopland DR, editor. Respiratory
health effects of passive smoking: lung cancer and other disorders. The
report of the US Environmental Protection Agency. USA: US Department of
Health and Human Services, Public Health Service, National Institutes of
Health; 1993. (Smoking and Tobacco Control. Monograph 4.) NIH Publication
8. Hackshaw AK, Law MR, Wald NJ. The accumulated evidence on lung
cancer and environmental tobacco smoke. BMJ 1997;315:980-8.
9. Lee PN, Forey BA. Misclassification of smoking habits as
determined by cotinine or by repeated self-report - a summary of evidence
from 42 studies. J Smoking-Related Dis 1995;6:109-29.
10. Lee PN. "Marriage to a smoker" may not be a valid marker of
exposure in studies relating environmental tobacco smoke to risk of lung
cancer in Japanese non-smoking women. Int Arch Occup Environ Health
11. Lee PN. Passive smoking and lung cancer: Strength of evidence
on passive smoking and lung cancer is overstated [Letter]. BMJ
12. Lee PN. Lung cancer and passive smoking: association an
artefact due to misclassification of smoking habits? Toxicol Lett
13. International Agency for Research on Cancer. Tobacco smoke and
involuntary smoking, Volume 83. Lyon, France: IARC; 2004. (IARC Monographs
on the evaluation of carcinogenic risks to humans.)
14. Lee PN, Forey BA, Fry JS. Revisiting the association between
environmental tobacco smoke exposure and lung cancer risk. III. Adjustment
for the biasing effect of misclassification of smoking habits. Indoor
Built Environ 2001;10:384-98.