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Int J Med Sci. 2009; 6(6): 329–337. Published online 2009 October 28. | PMCID: PMC2777271 |
Copyright © Ivyspring International Publisher. This is an
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(http://creativecommons.org/licenses/by-nc-nd/3.0/). Reproduction is permitted for
personal, noncommercial use, provided that the article is in whole, unmodified, and
properly cited. Comparative study of control selection in a national population-based case-control study: Estimating risk of smoking on cancer deaths in Chinese men Jingmei Jiang, 1 Boqi Liu, 2![[env]](/corehtml/pmc/pmcents/x2709.gif) Philip C. Nasca, 3 Wei Han, 1 Xiaonong Zou, 2 Xianjia Zeng, 1 Xiaobing Tian, 1 Yanping Wu, 2 Ping Zhao, 2 and Junyao Li 21. Department of Epidemiology and Medical Statistics, Peking Union Medical College 2. Department of Epidemiology, National Cancer Institute, Chinese Academy of Medical Sciences 3. Department of Epidemiology and Biostatistics, SUNY, Albany, the USA Received August 4, 2009; Accepted October 20, 2009. Purpose: To assess the validation of a novel control selection
design by comparing the consistency between the new design and a routine design
in a large case-control study that was incorporated into a nationwide mortality
survey in China. Methods: A nationwide mortality study was conducted during
1989-1991. Surviving spouses or other relatives of all adults who died during
1986-1988 provided detailed information about their own as well as the deceased
person's smoking history. In this study, 130,079 males who died of various
smoking-related cancers at age 35 or over were taken as cases, while 103,248
male surviving spouses (same age range with cases) of women who died during the
same period and 49,331 males who died from causes other than those related to
smoking were used as control group 1 and control group 2, respectively.
Consistency in the results when comparing cases with each of the control groups
was assessed. Results: Consistency in the results was observed in the analyses
using different control groups although cancer deaths varied with region and
age. Equivalence could be ascertained using a 15% criterion in most cancer
deaths which had high death rates in urban areas, but they were uncertain for
most cancers in rural areas irrespective of whether the hypothesis testing
showed significant differences or not. Conclusions: Sex-matched living spouse control design as an
alternative control selection for a case-control study is valid and feasible,
and the basic principles of the equivalence study are also supported by
epidemiological survey data. Keywords: case-control studies, epidemiologic methods, comparative study, smoking, Chinese men. One of the most important measures for ascertaining the impact of tobacco on a
population is the estimation of the mortality attributable to its use. To measure
this, a number of indirect methods of quantification are available. 1-5
However, although different methodologies are widely used, their methodological
foundations are all quite similar. Mainly they are based on the calculation of the
proportional attributable fraction. Thus, one of the limitations of the estimation
remained, because the proportional mortality analysis cannot estimate mortality from
the causes of death similar to those in the reference group. To improve the existing
calculations, a novel control group design was introduced in a previous study, 6 which replaced the regular reference group by
using the same sex surviving spouses of deceased people to calculate the mortality
risk rate. However, one question has been raised simultaneously, is it accurate and
validation? Although most clinical study activities are aimed at showing that equivalence can
also be claimed for generic versions of innovator drugs and for such diverse
entities as medical protocols, surgical techniques and medical devices, 7-10
there are no such standard criteria for how to evaluate and support such equivalence
claim in epidemiological survey data although many reports, 11-13 for example,
suggested that several well-designed valid case-control studies with consistent
results should be helpful in policy making when an answer is needed a short time. The purpose of this study was to apply the basic principles of a population-based
case-control study to assess the validation of the novel control selection design by
comparing the consistency between the new design and a routine control selection
design in a large case-control study that was incorporated into a nationwide
mortality survey in China in 1989-1991. As an example, we assessed the hazards of
tobacco use on smoking-related cancer deaths in Chinese adult men. We also offer
specific suggestions that we believe are useful in choosing controls within the
framework of the study principles. National Mortality Survey and Case-Control Study Design In 1989-1991, a large nationwide retrospective mortality survey was conducted in
China, which involved 103 study areas (24 major cities and 79 counties) and
approximately 1,000,000 adult deaths from all causes during the years
1986-1988. 1 We defined the total
population (close to 67 million) from which the mortality survey was conducted
as the study base. Cases and two groups of controls were obtained within the
study base: 130,079 males who died of smoking-related cancers at age 35 or over
were defined as cases. These diseases included: malignant neoplasm of the lips,
oral cavity, and larynx ((ICD-9: 140-149, 161, 3.9%), esophageal cancer (150,
15.2%), stomach cancer (151, 25.9%), liver cancer (155, 22.7%), lung cancer
(162, 27.2%), pancreatic cancer (157, 2.6%), prostate cancer (185, 0.7%), and
bladder cancer (188, 1.8%)). We combined the cancers of ICD-9 Codes
(140-149,161) into one group named “minor site cancers”
because the death rates for these cancers were too low for separate analysis.
Two different control groups were selected. The first group was recruited using
the novel design, which comprised all male surviving spouses (same age range
with cases) of any women who died (any cause of death) during those same years.
The second control group was chosen using the proportional mortality method and
comprised all men aged 35 or over who died from causes other than those related
to smoking. These diseases included: infectious and parasitic diseases (ICD-9:
001-009, 020-139, 7.8%), endocrine, metabolic, immune diseases (240-279, 5.6%),
blood and blood-forming organ diseases (280-289, 0.9%), mental disorders
(290-319, 3.3%), nervous system diseases (320-359, 3.1%), digestive system
diseases (520-579, 27.5%), genitourinary system diseases (580-608, 10.0%),
musculoskeletal and connective tissue diseases (710-739, 0.9%), injury and
poisoning (800-897, 33.1%), and other medical disorders (360-389, 680-709,
780-796, 7.9%). The selection of controls in this study was based on three
assumptions: (1) the individuals in both control groups had, in 1980, smoking
habits that were similar to those of the study base; (2) there was no
significant relationship between husband and wife in control group 1 in terms of
tobacco use; (3) the causes of death in control group 2 were unrelated to
tobacco exposure. Thus two separate population-based case-control studies were
formed within the study base with one group of cases and two different control
groups. The information on smoking history was obtained by interviews. We interviewed
informants (spouses or other relatives) of all deceased persons who described
their own smoking habits as well as those of their dead partners. These data
were used to determine whether people had ever smoked before 1980, a period of
time prior to the onset of their disease. A non-smoker was defined as a person
who had never smoked during his life or had only smoked infrequently at a young
age. Statistical Methods The relative risk (RR) for cancer deaths in smokers and non-smokers was estimated
by non-conditional logistic regression, adjusted for age (5-year age groups) and
the area of the residence. Confidence intervals (CIs) were used in this study, as in clinical trials, 7-10
to evaluate the equivalence of the two case-control studies in assessing the
risk of cancer deaths due to smoking. We first defined a range of equivalence as
an interval from -δ to δ (here, we defined δ=0.15).
We then simply checked whether the CI centered on the observed ratio of
 (the procedure of calculating CI is listed in
Appendix I) lay entirely between e -δ to
e +δ. If it did, equivalence was demonstrated; if it did not,
there was uncertainty regarding equivalence. Because  (when δ≤ 0.15), for convenience, the range of equivalence
was replaced by (1 - δ, 1 + δ). Thus the limits for
equivalence in this study were within 0.85 and 1.15. There were a total of 130,079 cases and 152,579 controls (103,248 in control group 1;
49,331 in control group 2) in our study. The basic characteristics of the cases and
controls, and relative risk of smoking-related cancer deaths among smokers by
comparison cases with each of the two control groups are shown in Table . Although data show that the relative risk
from smoking was greater for urban males than rural males, both study groups
revealed a consistent pattern of the effect of smoking on risk of cancer deaths. | TABLE 1Characteristics of cases and two control groups: Population-based
case-control study of smoking on risk of cancer deaths among Chinese men
1989-1991. |
Overall, 35.6% of the cancer cases (38.5% urban, 28.9% rural) were confirmed by
pathology, 56.3% (55.8% urban, 57.5% rural) were diagnosed by X-ray or by CT scan,
and 8.1% (5.7% urban, 13.5% rural) were diagnosed by clinical experience or by other
methods. The other methods group included patients who could not afford to go to
hospital, and when the families of these individuals were interviewed, a qualified
physician provided a diagnosis based on the patient's symptoms. The adjusted cancer RRs and their CIs had a high degree of overlap (with a small
standard error) between the two control groups in deaths from esophagus cancer,
stomach cancer, liver cancer, and lung cancer (Figure ) which had high incidence rates although the death rates from these
cancers varied by region and age (data not shown). When data were combined to
calculate the risk for all men, the RR (95%CI) with control groups one and two,
respectively, were: 1.96 (1.84-2.08) and 1.88 (1.79-1.97) for esophagus cancer; 1.29
(1.23-1.35) and 1.28 (1.24-1.34) for stomach cancer; 1.35 (1.31-1.39) and 1.33
(1.27-1.39) for liver cancer, 2.98 (2.88-3.08) and 2.95 (2.81-3.09) for lung cancer.
However, for other neoplasms which had low rates, the discrepancies in CIs were
increased because of a large standard error, and this was particularly true for
rural residents. The relative risks for cancer deaths between the two groups were also examined in
subgroups according to smoking history (Figure -). The result revealed a high
consistency with both control groups in most subgroups. In particular, with smokers
in both urban and rural areas, whose most recent habits involved only cigarettes,
significant dose-response relationships were found both in the duration of the
smoking habit and in daily cigarette consumption. For example, in urban men, the RR
(95%CI) for daily cigarette consumption <10, 10-19, ≥20 cigarettes
per day, respectively were: study group 1: 1.40 (1.34-1.45), 1.48 (1.44-1.52), and
2.25 (2.19-2.32); study group 2: 1.38 (1.29-1.49), 1.42 (1.35-1.50), and 2.12
(2.01-2.22). The absolute differences between the two groups in RRs ranged from 0.02
to 0.13. Furthermore, the RR (95%CI) for those who smoked ≥20 cigarettes
each day and had been smoking of for <20, 20-34, and 35+ years,
respectively, were: group 1: 1.73 (1.65-1.82), 2.26 (2.16-2.36) and 2.53
(2.45-2.62); group 2: 0.98 (0.90-1.06), 1.94 (1.78-2.12) and 3.06 (2.85-3.28). The
absolute differences in RRs ranged from 0.32 to 0.75, respectively (all trends test,
P < 0.001). There was a similar trend in rural men,
although the RRs were smaller than in urban men. The equivalence tests with a predefined interval (0.85-1.15) for various cancer
deaths were shown in Figure , and the
importance of not basing conclusions on statistical significance can also be seen in
this Figure. Any CI which does not overlap 1.0 corresponds to a statistically
significant difference between the two control groups. In the data shown for urban
males, the two estimates could be considered to have equivalence in esophagus
cancer, stomach cancer, liver cancer, pancreas cancer, lung cancer cancers, and
cancers on the minor sites, whereas the equivalence is uncertain for bladder cancer
and prostate cancer although all showed no statistically significant difference
between compared groups. For rural males, no equivalence could be ascertained
(except for liver cancer deaths) irrespective of whether the hypothesis testing
showing significant differences or not. Furthermore, when we combined all cancers to
test equivalence again, the results revealed equivalence in the two control groups
for both urban and rural males, with no statistically significant difference in
total cancer deaths between the compared groups. To our knowledge, this is the first nationwide study comparing different control
groups in a population-based case-control study, to assess the association between
smoking and death from various cancers in Chinese men. It shows that tobacco smoking
is associated with a moderate, but highly significant, increase in the risk of death
from various cancers. The consistency in results was observed in the analyses using
different control groups although in most cases the value of RR1 revealed a bit
greater than the value of RR2. Our study showed that equivalence can be ascertained
using the 15% criterion in those cancers which are very common in urban areas, but
they are uncertain for most cancers in rural areas irrespective of whether the
hypothesis testing showed significant differences or not between the two control
groups. Using sex-matched spouses as controls is an innovative design, and it is possible to
produce approximately random samples of the base population, because all deceased
people were approximately at random within the study base, as were their spouses.
The strengths of this design are: (1) it is possible to provide an alternative
method to give accurate estimate of early smoking-attributable mortality within a
nationwide level; (2) we may assess more relationships between one or more exposures
and various causes of death at one time, and use of a single control group for more
than one case series can lead to saving of money and time; 11-12 (3) all possible
confounding factors (known or unknown) and interaction effects between groups are
balanced by using large matching populations. In contrast, prospective studies take
years to mature, whereas retrospective methods require much less time. 12Three issues have been considered regard with the valid of our results: First, it
should be noted, if there is a strong association of smoking habits between couples,
the risks may be somewhat attenuated. In this study, the Kappa coefficient of
agreement test on smoking habits of couples were 0.076 in urban areas, and 0.163 in
rural areas, indicating a very weak association between couple's smoking habit.
Second, we compared the prevalence of smoking between male living spouses of women
who died of any cause and those spouses of women who died of some other causes other
than smoking related causes. The prevalence of smoking were 57.1% and 57.8%,
respectively, for urban male spouses, 64.1% and 63.6%, respectively for rural male
spouses indicating the relative risk analyses will not exaggerate the hazard of
tobacco. The third issue involves the validity of smoking data obtained from
surrogates. There are few former smokers in China (except those who stopped because
they were ill), 14-16 and family members were generally confident about whether
the dead person had smoked, although they were sometimes uncertain of the age when
smoking began. A validity study in Shanghai was conducted where the surviving spouse
was the informant and both husband and wife had reported their smoking habits in the
early 1980s. 17 Information obtained from the
spouse on the husband's smoking habits was highly consistent with information
provided directly by the husband. In this study, the very similar trends exit
between two groups in different subgroups (Figure -) indicating there is no obvious
disagreement in smoking history reported by proxy or by self-report. In this study, we attempt to apply the equivalence approach to assess the consistency
of different control selections with a control group determined by the proportional
mortality method as an 'active control' to evaluate the accuracy and feasibility of
the new control design. Although the dependence of RR1 and RR2 may have some
extended the length of CIs, which could lower the precise of CIs, some strengths are
still addressed: 7,13,18 First, a large
adequate sample size in each compared group can insure consistency between the
initial design and final analysis based on symmetric CIs for estimation using a
normal CI approach. Second, a large adequate sample size in each compared group will
make a high probability (1- β, β is type II error) to insure that
the upper/low limit of CIs will not excess the selected criterion (±15%),
i.e.,  , where 1-β is statistical power. 19 Third, we selected control group 2 as an
'active control' group which is reliant on an implicit 'historical control
assumption'. One cannot automatically assume that the active control group will be
effective under a new set of study conditions by virtue of the fact that it was
previously proven to be efficacious for a given indication. Our findings revealed
that better equivalence exists in urban than in rural areas, and for cancers with a
high death rate than for 'rare' cancers. The possible explanations may be: (1) some
rare cancer death rates are too low to be stable; (2) a difference in the accuracy
of certificated cause of death between urban and rural counties; (3) large
fluctuations in Chinese social circumstances during the decades before 1980, with
large changes in cigarette sales per adult, meaning that middle-aged cigarette
smokers who died in 1986-1988 were unlikely to have had consistent tobacco
consumption since early adult life: this is particularly true in large rural areas.
Our findings also confirmed the fact that the conventional statistical significance
test has little relevance in equivalence testing. Failure to detect a difference
between two RRs does not imply equivalence, and a statistically significant
difference does not mean it is not equivalent. It should be noted that absolute
equivalence can never be demonstrated, and it is only possible to assert that the
true difference is unlikely to be outside a range, which depends on the size of the
trial and specified probabilities of error. 13,18In the methodological areas of control selection, it is widely accepted that the
inclusion of multiple control groups selected by different criteria is preferable to
only one control group. 20-23 Multiple control groups provide checks on
potential biases, and afford the opportunity to demonstrate consistency in the
findings. In our study, a series of consistent patterns of results was obtained from
control group 1 and group 2. Although selection biases could produce similar but
erroneous results, this is most unlikely because two control groups were selected by
completely different means in this study. However, it should be noted that there is
no 'gold standard' in epidemiological surveys although we selected controls by the
proportional mortality method as the 'active controls.' Any control selection has
its own strength or weakness. We used the proportional mortality method, for
example, to create an 'active control,' and the main strengths of such controls is
that the criteria for eligible controls can be established conveniently; any
omissions typically will not lead to selection bias, since the accuracy of the
system for registering deaths from most causes is unlikely to vary substantially
with cause of death. 11,18 Furthermore, any recall bias affecting assessment of smoking
habits in the cases should similarly affect assessment of smoking habits in the
control group, 1 however, insisting on a dead
control group violates the study base principle, since the base consists of living
subjects. In the same situation, when we use a sex-matched living spouse control
design, we may explore smoking hazards more widely (known or unknown) and
accurately. However, when information is obtained from a surrogate because the case
is dead, using a living control sampled properly from the base can breach the
principle of comparable accuracy. 11Some limitations of this study must also be considered when interpreting the results.
First, only 90% of deaths in the study base were recruited, thus selection bias may
have some effect on our results. Second, 5.7% of urban and 13.5% of rural cancer
deaths in our study were diagnosed only by clinical experience, or inference after
dying, which may result in misclassification, and this is particularly true in rural
areas, although our design included a greater urban population than rural
population, which countered the difference in accuracy of the death certificate.
Third, social class, which is also associated with both smoking and cancer deaths,
was not measured in this study, and the separate calculation of risk patterns in
urban and rural areas was used as a surrogate analysis by socioeconomic status. In conclusion, the basic principles of equivalence are also supported by
epidemiological survey data. The sex-matched living spouse control design as an
alternative control selection for a nationwide population-based case-control study
is valid and feasible, and can produce highly acceptable research results for a
fixed expenditure of time and resources. We thank Cancer Research UK, the UK Medical Research Council, the US National
Institutes of Health, the Chinese Ministry of Health, and the Chinese Academy of
Medical Sciences who supported the original survey. We thank Professor Richard Peto, who gave us great support for the project. The cooperation of the local government, the thousands of doctors, nurses, and other
field workers who conducted the surveys, and the million interviewees are greatly
acknowledged. Appendix I - Procedure of calculating CI 1. Liu BQ, Peto R, Chen ZM. et al. Emerging tobacco hazards in China 1. Retrospective proportional
mortality study of one million deaths. Br Med J. 1998;317:1411–22. [PMC free article] [PubMed] 2. Thun MJ, Apicella LF, Henley SJ. Smoking vs other risk factors as the cause of
smoking-attributable deaths. JAMA. 2000;284:706–12. [PubMed] 3. Rivara FP, Ebel BE, Garrison MM. et al. Prevention of smoking-related deaths in the United States. Am J Prev Med. 2004;27:118–25. [PubMed] 4. Peto R, Lopez AD, Boreham J. et al. Mortality from tobacco in developed countries: indirect
estimation from national vital statistics. Lancet. 1992;339:1268–78. [PubMed] 5. Sitas F, Urban M, Bradshaw D. et al. Tobacco attributable deaths in South Africa. Tobacco Control. 2004;13:396–99. [PMC free article] [PubMed] 6. Jiang J, Liu B, Sitas F. et al. Smoking-attributable deaths and potential years of life lost from
a large, representative study in China. Tobacco control Sep. 2009 [Epub ahead of print] 7. Jones B, Jarvis P, Lewis JA. et al. Trail to assess equivalence: the importance of rigorous methods. BMJ. 1996;313:36–39. [PMC free article] [PubMed] 8. Greene WL, Concato J, Feinstein AR. Claims of Equivalence in Medical Research: Are They Supported by
the Evidence? Ann Intern Med. 2000;132:715–22. [PubMed] 9. Fuller RW, Hallett C, Dahl R. Assessing equivalence of inhaled drugs. Respir Med. 1995;89:525–27. [PubMed] 10. Dong BJ, Hauck WW, Gambertoglio JG. et al. Bioequivalence of generic and brand-name levothyroxine products
in the treatment of hypothyroidism. JAMA. 1997;277:1205–13. [PubMed] 11. Wacholder S, Silverman DT, McLaughlin JK. et al. Selection of Controls in Case-Control Studies: III. Design
Options. Am J Epidemiol. 1992;135:1042–50. [PubMed] 12. Lopez AD. Counting the dead in China. Measuring tobacco's impact in the
developing world. Br Med J. 1998;317:1399–1400. [PMC free article] [PubMed] 13. Schuirmann DJ. A comparison of the two one-sided tests procedure and the power
approach for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm. 1987;15:657–80. [PubMed] 14. Weng XZ. Report on the 1984 Chinese national smoking prevalence survey. Beijing: People's Medical Publishing House; 1988. 15. Yang GH. Report on the 1996 nationwide survey of smoking prevalence. Beijing: China Science and Technology Press; 1997. 16. Gu D, Wu X, Reynolds K. et al. Cigarette smoking and exposure to environmental tobacco smoke in
China: the international collaborative study of cardiovascular disease in
Asia. Am J Public Health. 2004;4:1972–6. [PMC free article] [PubMed] 17. Deng J. The prevalence of smoking habit among 110 000 adult residents in
urban Shanghai [in Chinese] Zhonghua Yu Fang Yi Xue Za Zhi. 1985;5:271–4. [PubMed] 18. Dunnett CW, Gent M. Significance testing to establish equivalence between treatments,
with special reference to data in the form of 2x2 tables. Biometrics. 1977;33:593–602. [PubMed] 19. Bernard R Rosner. Fundamentals of Biostatistics. Brooks Cole. 2005. 20. Ibrahim MA, Spitzer WO. The case-control study: the problem and the prospect. J Chronic Dis. 1979;32:139–44. [PubMed] 21. Horwitz RI, Feinstein AR. Alternative analytic endometrial cancer. N Engl J Med. 1978;299:1089–94. [PubMed] 22. Hulka BS, Grimson RC, Greenberg BG. et al. “Alternative” controls in a case-control
study of endometrial cancer and exogenous estrogen. Am J epidemiol. 1980;112:376–387. [PubMed] 23. Boissel JP, Collet JP, Lion L. et al. A randomized comparison of the effect of four antihypertensive
monotherapies on the subjective quality of life in previously untreated
asymptomatic patients: field trial in general practice. The OCAPI Study
Group. Optimiser le Choix d'un Anti-hypertenseur de Premiere Intention. J Hypertens. 1995;13:1059–67. [PubMed]
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