Periodontology 2000, Vol.

30, 2002, 5160

Printed in Denmark. All rights reserved

Copyright C Blackwell Munksgaard 2002

PERIODONTOLOGY 2000
ISSN 0906-6713

Periodontitissystemic disease
associations in the presence of
smoking causal or
coincidental?
P. P. H, M. D, C. S & T. A. DR

No current issue in periodontal research is more visible or controversial than the relationship between
periodontitis and systemic diseases. Although there
is some awareness that the observed associations
could be coincidental, as a result of confounders
such as age and smoking, the full impact such confounding can have, especially without adequate statistical adjustment, does not seem to be appreciated.
Four lines of evidence suggests that the observed
periodontitissystemic disease associations are, in
part, a result of confounding by smoking the inability to distinguish the effect of smoking on periodontitis from the effect of smoking on systemic diseases. First, no periodontitissystemic disease associations have been identified among neversmokers. Second, periodontitis and smoking mimic
one another with respect to the types of diseases
with which they are associated (e.g. lung cancer and
Parkinsons disease). Third, only studies with inadequate adjustment for smoking report significant
periodontitissystemic disease associations. Lastly,
elimination of dental infection, unlike smoking cessation, does not reduce coronary heart disease risk.
A systematic evaluation of the periodontitissystemic associations among healthy never-smokers
would help to indicate in which direction, if any, periodontitissystemic disease research should progress.

Smoking, the epidemiologists

perspective
Individuals with periodontitis are more likely to be
current or past cigarette smokers than individuals

without periodontitis (11). Therefore, when individuals with and without periodontitis are compared it
is to be expected that individuals with periodontitis
will have more smoking-related diseases, such as
coronary heart disease, lung cancer, low-birthweight babies etc., than individuals without periodontitis. The comparison between individuals with
and without periodontitis with respect to the occurrence of systemic diseases is said to be biased because of the unequal distribution of smoking in the
two groups. In epidemiological terminology, smoking is referred to as a confounder; smoking spuriously inflates the association between periodontitis
and smoking-related diseases because it is causally
related to both, regardless of whether periodontitis
and the systemic diseases are causally related to
each other.
Statistical adjustment or control for confounding
is possible using different statistical methods such as
stratification or covariance adjustment in statistical
models. Such statistical adjustment can be used to
eliminate some but (and this is a critical point) not
all of the bias caused by the higher prevalence of
smokers among individuals with periodontitis. The
goal of statistical adjustment is to make the two
compared groups (individuals with and without
periodontitis) similar with respect to the true lifelong exposure to any form of tobacco smoking. This
true life-long exposure requires detailed information
on many variables such as the dose (amount of tobacco used), chemical composition of smoke (use of
filter, type of tobacco) and smoking intensity
(amount of smoke inhaled) during a persons entire
lifetime.

51

Hujoel et al.

Such detailed information is almost impossible to

obtain and, unavoidably, imperfect life-long tobacco
smoking measures are used. The imperfect measures
are typically derived from questionnaires where individuals are asked to recall the several dimensions of
their tobacco history during their life. This information from questionaires is subsequently condensed into one or more smoking variables that are
included in the analyses. The imperfect smoking
questionnaires (23), the recall bias (29), the inability
to ask questions or otherwise obtain information on
important characteristics of smoking (e.g. tobacco
content) (9, 32), and the difficulty in specifying a correct statistical model (a truism best illustrated by
McCullagh & Nelders first principle of statistical
modeling all models are wrong) (18, 21) all make
it virtually impossible to have perfect statistical adjustment for smoking.
It should not be surprising therefore that individuals with and without periodontitis cannot be made
exactly comparable with respect to the true lifelong smoking exposure using statistical adjustment
techniques. Smoking characteristics not captured in
the statistical models will be found more often
among individuals with periodontitis than among
individuals without periodontitis. As a result, the incidence of smoking-related systemic diseases will remain spuriously inflated among individuals with
periodontitis. Two extremes exist. If, at one extreme,
many important smoking characteristics are not
captured and the smoking prevalence is high, the
bias is maximized and periodontitis appears strongly
associated with smoking-related diseases. Such an
extreme may be present when investigators do not
include smoking measures in the statistical models
(7) and when the smoking prevalence in the studied
population is high (12). At the other extreme, smoking will minimally bias the periodontitissystemic
disease associations when smoking prevalence is low
and when comprehensive smoking measures are included in the analyses. Some epidemiological
studies fall between these two extremes; some approximate smoking measures are available, and the
association between periodontitis and smoking-related diseases remains substantially inflated.
Wherever past or current smokers are included in
the analyses, biased periodontitis systematic disease associations will be reported. Therefore, primary analyses should be limited to healthy neversmokers both because smoking is such a strong risk
factor, and because the magnitude of smoking cannot be well measured. The fundamental rationale for
the exclusion of smokers is that it is not possible to

52

adjust for the overwhelming impact of smoking on

the studied association. The inclusion of smokers in
the analyses, even with rigorous adjustment for
smoking history, becomes inappropriate because it
leaves too much residual bias (30). A recommendation to eliminate smokers from primary analyses has
been made in obesity research where statistical adjustment for smoking is considered inadequate, because the association of smoking with obesity cannot be separated from the effect of smoking on illness and death (25). Also, in the study of the
associations between Chlamydia pneumoniae and
coronary heart disease, the findings among neversmokers are drastically different from the findings
among smokers (28). Similarly, periodontitissystemic disease associations should be studied primarily among never-smokers.
Limiting the analyses to healthy never-smokers
provides important advantages above and beyond
control for smoking. Smoking is strongly related to
other factors such as health awareness, lifestyle, education, socio-economic status and possibly other unknown factors that are important determinants of systemic disease. By limiting an analysis to healthy
never-smokers, it becomes controlled for both known
and unknown factors that may be at least as challenging to control for as the control for smoking itself.
Four lines of evidence indicate that the effect of
smoking on periodontitis cannot be distinguished
from the effect of smoking on systemic diseases:
O periodontitissystemic disease associations have
not been identified among never-smokers.
O periodontitis and smoking are associated with
similar health risks.
O conflicting study results can be explained in terms
of statistical adjustment for tobacco smoking.
O dental infection elimination through complete
tooth removal, unlike smoking cessation, does not
reduce health risks.

The periodontitissystemic disease

associations among never-smokers
We tested the hypothesis that the magnitude of the
periodontitissystemic disease associations is influenced by the prevalence of smokers and the degree
of adjustment for smoking. Table 1 shows a summary
of the data on the periodontitissystemic disease associations in three groups: smokers only, neversmokers and smokers combined (but with adjust-

Periodontitis, systemic diseases and smoking

ment for smoking history), and never-smokers exclusively. The association between periodontitis and
the systemic disease is reported using hazards ratios.
A hazards ratio of 1.0 indicates a lack of association,
a value above 1.0 indicates an elevated risk and a
value below 1.0 indicates a protective effect of periodontitis. If smoking is the driving factor behind the
periodontitissystemic disease associations, the
magnitude of the associations should decrease as
the control for smoking increases and the prevalence
of smoking decreases.

Periodontitis and chronic obstructive

pulmonary disease (COPD)
Among past and current smokers, periodontitis significantly increased the risk for COPD [hazard ratio
(HR) 1.52, 95% confidence interval 1.211.91]. When
the analysis included past, current, and neversmokers with adjustment for reported smoking dose
and duration, the HR for COPD decreased by 7% (HR
1.42; 95% confidence interval 1.161.72). Finally,
when the analysis was limited to never-smokers,
periodontitis was associated with a small and insignificant increased risk for COPD (HR 1.24; 95% confidence interval 0.901.72).

Periodontitis and lung cancer

Among past and current smokers, periodontitis significantly increased the risk for lung cancer (HR 1.94;
95% confidence interval 1.143.30). When the analysis included never-, past, or current smokers, with
adjustment for smoking the HR for lung cancer associated with periodontitis decreased by 49% (HR

1.48; 95% confidence interval 0.882.50). When the

analysis was limited to never-smokers, the opposite
association was present. Periodontitis was associated with a decreased risk for lung cancer, not an
increased risk (HR 0.58; 95% confidence interval
0.122.78).

Periodontitis and stroke

Among past and current smokers, periodontitis marginally increased the risk for stroke (HR 1.19; 95%
confidence interval 0.841.87). When the analysis included never-, past or current smokers with adjustment for smoking, the HR for stroke associated with
periodontitis decreased by 8% (HR 1.09; 95% confidence interval 0.821.45). Finally, when the analysis
was limited to never-smokers, periodontitis increased the HR for stroke by 11% (HR 1.11; 95% confidence interval 0.791.57). These findings differ
from previously reported results (31) and potential
reasons for these differences are discussed in the Appendix.

Periodontitis and coronary heart disease

(CHD)
Among past and current smokers, periodontitis significantly increased the risk for CHD by 26% (HR
1.26; 95% confidence interval 1.021.56). Among
past, current and never-smokers the HR for CHD associated with periodontitis was 1.13 (95% confidence
interval 0.951.34). Finally, when the analysis was
limited to never-smokers, the HR for CHD associated
with periodontitis became insignificant and indis-

Table 1. Adjustment for tobacco smoking and the magnitude of periodontitissystemic disease associations
Excellenta

Goodb

Poorc

1.24 (0.901.72)

1.42 (1.161.72)

1.52 (1.211.91)

Lung cancer

0.58 (0.122.78)

1.48 (0.882.50)

1.94 (1.143.30)

1.11 (0.791.57)

1.09 (0.821.45)

1.19 (0.841.73)

1.04 (0.821.32)

1.13 (0.951.34)

1.26 (1.021.56)

Disease
COPDd
e

Stroke
g

CHD
a

Excellent control for smoking refers to analyses limited to never-smokers (duration of smoking 0 years).
b
Good control for smoking was obtained by including smokers in the analyses (50% of the population) and adjusting the analyses for the logarithm of smoking
duration and the number of cigarettes per day
c
Poor control for smoking was obtained by limiting the analyses to smokers and not adjusting the analyses for smoking duration or dose.
d
COPD, chronic obstructive pulmonary disease (analyses were adjusted for age, age squared, race, poverty index, education, smoking duration and dose, and
vitamins A and C).
e
Lung cancer (analyses adjusted for the same variables as COPD analyses).
f
Stroke (analyses were adjusted for same variables as CHD analyses).
g
CHD, coronary heart disease [analyses adjusted for age, age squared, gender, race (two indicator variables for African American and other), poverty index,
marital state, education, and an interaction term for marital state and gender, diastolic blood pressure, systolic blood pressure, serum cholesterol, diabetes,
log (height), log (weight), log (number of glasses per day), physical activity (indicator variable for heavy recreational or nonrecreational physical activity), and
nervous breakdown and sampling design]. No adjustment for sampling weights was performed. The results differ by 1% from a previous report (11) (1.13 vs.
1.14) because 14 individuals missed in the previous analyses were included in the current analyses.

53

Hujoel et al.

tinguishable from a no-risk increase (HR 1.04; 95%

confidence interval 0.821.32).
The observed trends for these four systemic diseases are consistent with the hypothesis that imperfect adjustment for smoking history is inducing spurious associations between periodontitis and smoking-related
diseases.
Among
never-smokers,
periodontitis was either not associated, or was
weakly associated, with systemic diseases. None of
the periodontitissystemic disease associations were
statistically significant among never-smokers. When
both smokers and nonsmokers were included in the
analyses, the magnitude of the association increased
for three of the four diseases, and one of the four
reported periodontitissystemic disease associations, COPD became significant. Finally, when the
analyses were limited to smokers, the magnitude of
the association increased for all four diseases and
three of the four diseases become significantly associated with periodontitis (COPD, lung cancer and
CHD). This direct relationship between the strength
of the periodontitissystemic disease associations
and the level of adjustment for smoking indicates
that smoking causes strong biases in the periodontitissystemic disease associations.

Periodontitis and smoking are

associated with similar health risks
Smoking is most strongly associated with lung cancer, followed by COPD, CHD and stroke (Table 2).
Smoking is associated with a decreased risk for Parkinsons disease. Periodontitis mimics this pattern
step by step: periodontitis is most strongly associ-

ated with lung cancer, followed by COPD, CHD and

stroke.
If periodontitissystemic disease associations are
a result of incomplete adjustment for smoking, other
periodontitissystemic disease associations should
become predictable. Because smoking is negatively
associated with Parkinsons disease, periodontitis
should be also. An evaluation of this association
within NHEFS indicated that periodontitis was indeed associated with a decreased risk for Parkinsons
disease. Is it just an unusual coincidence that periodontitis mimics smoking-related diseases not only
for the harmful trends, but also for the beneficial
ones?
If periodontitis were an independent causal risk
factor for the same diseases that smoking caused,
the chance that periodontitis and smoking would
mimic each other with respect to the patterns
(rank order) of strengths of association in the five
diseases listed in Table 2 is less than 0.008. In other
words, the probability of periodontitis and smoking
being ranked similarly with respect to the strength
of their associations to these five systemic diseases
is 1 out of 120. (Five distinct systemic diseases
can be ranked in 5 4 3 2 1 unique ways. The
chance that both smoking and periodontitis will
rank the five systemic diseases in the exact same
way is 1 in 120.) Furthermore, thus far, smoking
and periodontitis have both been associated (positively or negatively) with the same seven diseases.
[In addition to the diseases identified within the
NHEFS population, periodontitis has been associated with low birth weight (6) and diabetes, two
diseases related to smoking. Smoking, especially in
the third trimester, has been associated with increased risk for low birth weight (2628). Similarly,

Table 2. Smoking- and periodontitis-related systemic diseases; similarity of the pattern of the associations
Diseases

Periodontitis
associated

Smoking identified
as a causal factor

Periodontitissystemic
disease association

Smokingsystemic
disease association

Lung cancer

&

&

1.48 (0.882.50)

7.11 (3.3115.26)

COPD

&

&

1.42 (1.161.72)

2.63 (2.243.09)

CHD

&

&

1.13 (0.951.34)

1.41 (1.201.66)

Stroke

&

&

1.09 (0.821.45)

1.26 (0.961.67)

Parkinsons diseasea

&

&

0.62 (0.341.14)

0.72 (0.411.25)

Low birth weight

&

&

Diabetes

&

&

COPD, chronic obstructive pulmonary disease; CHD, coronary heart disease.

a
Analyses adjusted for age, age squared, gender, race, poverty index, education, diabetes, log(duration of smoking), and smoking dose.

54

Periodontitis, systemic diseases and smoking

there is increasing evidence that smoking is causally related to diabetes (29).]

While we have not screened all possible diseases
to confirm that periodontitis and smoking are always
associated with the same diseases, if the trend we
have observed thus far continues, the probability
that two independent factors are always associated
with the same diseases in the same order of magnitude would be minuscule (orders of magnitude
smaller than 0.008).
Providing an explanation for this striking resemblance in the pattern of the observed periodontitis
systemic disease associations is simple from the
noncausal perspective (13). If a higher prevalence of
uncontrolled smoking characteristics is present
among individuals with periodontitis, periodontitis
will mimic smoking with respect to the strengths by
which it is associated with systemic diseases. This
explanation is logical and biologically plausible; because of inadequate adjustment for smoking histories, periodontitis itself becomes a ghost marker for
the unadjusted (residual confounding) effect of tobacco smoking.
A causal interpretation of the evidence would be
that periodontitis is an independent causal factor
that just happens to cause and prevent the same diseases as smoking with relative orders of magnitude
of associations that just happen to be identical when
ranked from strongest association (lung cancer) to
weakest association (CHD). As indicated earlier, the
probability of this occurrence is minuscule. The
similarity of disease patterns indicates that many of
the observed periodontitissystemic disease associations are probably spurious and are a result of the
residual confounding effect of smoking.

Conflicting study results can be

explained in terms of statistical
adjustment for tobacco smoking
When findings differ substantially from one study to
the next, potential causes for the study-to-study differences should be investigated. We evaluated the
extent to which the adequacy of adjustment for
smoking could explain conflicting periodontitis
CHD associations (13). Most of the published studies
adjusted for smoking in different ways, so we categorized a study as having good adjustment for
smoking when the number of cigarettes smoked per
day (sometimes referred to as smoking dose) was
taken into account in the analyses. When a study did

not take into account the number of cigarettes

smoked per day, or when a study did not take into
account smoking at all, the study was categorized as
poorly adjusted.
There have been a total of nine cohort studies
published on the periodontitisCHD associations,
with the findings summarized in Table 3. These
studies were published between 1993 and 2001 and
have reported data from 97,685 individuals with 4520
events. Four of the nine studies had poor smoking
adjustment, while five had good smoking adjustment. The assessments of heterogeneity and summary descriptive statistics should be considered approximate both because three studies derived data
from the same populations, and because the definitions of cardiovascular disease and periodontitis
varied between studies.
The nine studies varied considerably with respect
to the reported association between periodontitis
and CHD. Is this large study-to-study variability a result of the large differences that existed in the quality
of the adjustment for smoking? Periodontitis was not
significantly associated with CHD (HR 1.05; 95%
confidence interval 0.961.15) among those studies
that provided a good adjustment for smoking dose.
In contrast, periodontitis was significantly associated with CHD in the four studies that either did not
adjust for smoking or adjusted crudely (HR 1.25; 95%
confidence interval 1.151.37). Lack of control for

Table 3. Control for smoking dose and the magnitude of the periodontitiscoronary heart disease association
Control
for smoking
dose

Study
referencea

Hazard ratio or
relative risk (95%
confidence interval)

No

(19)

1.21 (1.081.36)

No

(7)

2.68 (1.305.50)

No

(1)

1.50 (1.042.14)

No

(5)

1.25 (1.061.48)

Summary

1.25 (1.151.37)

Yes

(12)

0.97 (0.721.31)

Yes

(22)

1.37 (0.802.35)

Yes

(17)

1.04 (0.861.25)

Yes

(10)

1.01 (0.881.15)

Yes

(11)

1.13 (0.951.34)

Summary

1.05 (0.961.15)

See reference section to locate bibliographical reference corresponding to

the number.

55

Hujoel et al.

smoking dose provides a plausible explanation for

why small, but statistically significant, periodontitis
CHD associations are only present for studies that
poorly adjust for smoking.
It is important to note that even studies that had
a good adjustment for smoking leave residual
smoking-related biases. Detailed statistical adjustment based on self-reported smoking measures is
impossible. It has been demonstrated that the inadequate capture of the smoking effects by the selfreports (as opposed to more objective measures
such as serum cotinine levels) can induce a high
proportion of spurious positive associations of periodontitis with smoking-related systemic diseases in
the absence of such true relationships (i.e. falsepositive associations) (27). Rigorous control for
smoking can only be obtained by limiting the analyses to never-smokers.

specialist. In addition, this hypothesis is at the basis

of a multicenter randomized clinical trial in 900 subjects where the effect of periodontal treatments on
the secondary prevention of cardiovascular events
will be evaluated. This movement towards focusing
on secondary prevention of CHD by site-specific
periodontal treatments is based more on hope than
on evidence.
There is certainly hope that secondary prevention
of CHD events can occur through periodontal treatment. If so, it would create a potential line of research that would probably attract additional
funding because of the more serious consequences
of cardiovascular disease on morbidity and mortality. Current epidemiological evidence does not
support the hope that periodontitis plays a role in
secondary heart disease prevention. A large and
well-controlled cohort study in the US population
suggests that periodontitis does not increase the risk
for secondary heart disease events (13). Individuals
with periodontitis and pre-existing heart disease
were found to be at the same risk for developing a
secondary heart disease event as the individuals with
pre-existing heart disease but without periodontitis.
These data are hardly encouraging for seeing a beneficial result in a randomized trial that focuses on secondary CHD events.
There is also hope that periodontal treatments can
reverse an increased CHD risk. This hope is not supported by evidence. Findings from the same cohort
study indicated that a definitive, irreversible, and
complete elimination of all dental infections by extraction does not decrease CHD risk (12) (Table 4).
When followed for 20 years, the hazard for a CHD

Dental infection elimination

through complete tooth removal,
unlike smoking cessation, does not
reduce health risks
It has been suggested that periodontal treatments
may lower the risk for adverse health outcomes (4).
In particular, a popular current hypothesis is that the
treatment of periodontal infections in individuals
with pre-existing heart disease decreases the risk for
future CHD events. This hypothesis is the basis for
recommending that individuals with existing cardiovascular disease should visit a periodontal medicine

Table 4. Hazard ratios (HRs) for coronary heart disease (CHD) events and CHD mortality associated with elimination of dental infectionsa
HR

95% CI

HR

95% CI

DMG/SES

CVR1

CVR2

1.52

1.351.70

1.61

1.351.92

1.08

0.951.22

1.10

0.911.33

1.04

0.901.20

0.99

0.791.25

1.02

0.871.19

1.02

0.791.31

1.02

0.861.21

1.02

0.811.29

Sample design

HRs larger than 1 indicate a harmful effect of dental infection elimination, less than 1 indicate that dental infection elimination reduces CHD risk.
a
Coronary heart disease (CHD) events include revascularization, nonfatal myocardial infarction, and fatal CHD. CI indicates confidence interval. Comparisons
are made to individuals with a chronic dental infection, periodontitis. Individuals with periodontitis had a periodontal pocket with attachment loss (i.e. not
merely a deepened gingival crevice because of swelling in the free gingiva).
DMG/SES: age, age squared, gender, race (two indicator variables for African American and other), poverty index, marital state, education, and an interaction
term for marital state and gender.
CVR1: log(smoking duration), number of cigarettes per day, diastolic blood pressure, systolic blood pressure, serum cholesterol, diabetes.
CVR2: height, weight, an interaction term for height and weight, log(number of glasses per day), physical activity (indicator variable for heavy recreational or
nonrecreational physical activity), nervous breakdown.
Sample Design: multistage cluster sampling without replacement.

56

Periodontitis, systemic diseases and smoking

event among edentulous individuals did not decrease when compared to individuals with periodontitis. If a complete, definitive and irreversible
elimination of dental infection through complete
tooth removal does not lower CHD risk, why would
an incomplete, imperfect and reversible decreasing
of the bacterial load by means of periodontal treatments decrease CHD risk? Some have offered the explanation that the risk, once established, is not reversible and therefore primary periodontitis prevention trials, rather than secondary prevention, should
be initiated (16). An alternative explanation of this
evidence is that, unlike smoking cessation, dental infection elimination has no impact on CHD incidence
(13).
The current intervention evidence is consistent
with the hypothesis that dental infections occur coincidentally with, but are not causal for, increased
cardiovascular risk. Periodontitis is known to be
strongly associated with smoking, which also elevates systemic disease risks. The elimination of dental
infections may not reduce cardiovascular disease
risk because the elimination of dental infections
does not necessarily have an effect on smoking
habits.

Periodontitissystemic disease
studies need to be limited to neversmokers
Substantial evidence indicates that periodontitis
systemic disease associations are inflated because
the effect of smoking on periodontitis cannot be separated from the effect of smoking on systemic diseases. The bias caused by smoking explains why the
complete elimination of dental infections does not
decrease CHD risk (12) and why no significant periodontitissystemic disease associations have been
identified among never-smokers. In addition, the
bias caused by smoking explains why in populations
with a high smoking prevalence, periodontitis behaves like a surrogate measure for smoking being
associated with an elevated risk for the smoking-related diseases, such as COPD, and with a decreased
risk for a disease against which smoking protects,
Parkinsons disease. It is obviously ludicrous to suggest inducing periodontitis to treat Parkinsons disease, but is the epidemiological evidence for treating
periodontitis to prevent secondary CHD events any
better? While methodological issues other than
smoking remain important (13), the next step in re-

search in the periodontitissystemic disease relationship should be to evaluate systematically the

periodontitissystemic disease associations among
healthy never-smokers to determine in which direction, if any, future research should progress.
The recommendation to restrict periodontitissystemic disease research to never-smokers is a standard epidemiological research approach that is used
whenever there is a strong confounding factor the
presence or absence of which is easily determined,
but of which the magnitude cannot be well-measured. Smoking definitely falls into this category. In
obesity research, adjustment for smoking, because
of its complexity, is considered impossible and inappropriate, and the primary analyses are consequently limited to healthy never-smokers (3, 25, 26,
30). In diet research, lack of rigorous control for
smoking has led to significant biases regarding the
benefits of fruits and vegetables on lung cancer prevention (6, 13). In Chlamydiae pneumoniaeCHD research, findings among nonsmokers were diametrically opposed to findings among smokers (28). The
recommendation therefore to evaluate periodontitissystemic disease associations among
healthy never-smokers is not unusual or without
precedent. It is a recommendation that is consistent
with epidemiological research in chronic disease
areas other than periodontitis.
An acid test for any scientific hypothesis is the
ability to predict correctly associations that have
hitherto been unobserved. If inadequate control for
the effects of smoking is partly responsible for the
currently observed periodontitissystemic disease
associations, then associations of periodontitis with
other smoking-related diseases, which have not yet
been identified, can be predicted. By successfully
predicting that lung cancer and Parkinsons disease
were associated with periodontitis, the hypothesis
that smoking induces spurious periodontitissystemic disease associations is further confirmed. We
can more confidently conclude that smoking is a
major cause of spurious periodontitissystemic disease associations because the hypothesis of incomplete control for smoking correctly predicts novel associations.
The possibility of smokingperiodontitis interactions cannot be excluded. Periodontitis may cause
systemic diseases only in the presence of smoking;
or, periodontitis may worsen the ill effects of smoking on systemic health (15). While this hypothesis
may be worthy of further investigation, the public
health importance is unclear. It has been suggested
that it is absurd for smokers in the West to worry

57

Hujoel et al.

about anything except stopping smoking (24). The

adverse health effects of smoking are so overpowering that concerns regarding other risk factors,
such as diet or exercise, in the presence of smoking
are clearly of only minor importance. Recommending periodontal treatment in order to lower the
risk for CHD in a smoker would seem of little potential benefit to the patient, even if the periodontitis
CHD association were assumed to be causal, unless
the patient stopped smoking.
We recommend initiating a systematic examination of periodontitissystemic disease associations
among healthy never-smokers. In addition, future
reports on the periodontitissystemic disease associations need to report the periodontitissystemic disease associations among healthy never-smokers. A
synthesis of this information could provide a rational
basis to determine in which direction, if any, periodontitissystemic disease research should proceed.

References
1. Beck J, Garcia R, Heiss G, Vokonas PS, Offenbacher S. Periodontal disease and cardiovascular disease. J Periodontol
1996: 67: 11231137.
2. Breslow RA, Wideroff L, Graubard BI, Erwin D, Reichman
ME, Ziegler RG, Ballard-Barbash R. Alcohol and prostate
cancer in the NHANES I epidemiologic follow-up study.
First National Health and Nutrition Examination Survey of
the United States. Ann Epidemiol 1999: 9: 254261.
3. Calle EE, Thun MJ, Petrelli JM, Rodriguez C, Heath CW, Jr.
Body-mass index and mortality in a prospective cohort of
US adults. N Engl J Med 1999: 341: 10971105.
4. Cowley G. The Heart Attackers. Newsweek 1997: 130: 46
48.
5. DeStefano F, Anda RF, Kahn HS, Williamson DF, Russell
CM. Dental disease and risk of coronary heart disease and
mortality [see comments]. BMJ 1993: 306: 688691.
6. Feskanich D, Ziegler RG, Michaud DS, Giovannucci EL,
Speizer FE, Willett WC, Colditz GA. Prospective study of
fruit and vegetable consumption and risk of lung cancer
among men and women. J Natl Cancer Inst 2000: 92: 1812
1823.
7. Genco R, Chadda S, Grossi S, Dunford R, Taylor G, Knowler W, Pettitt D. Periodontal disease is a predictor of cardiovascular disease in a Native American Population. J Dent
Res 1997: 76: 408 (Abstract 3158).
8. Graubard BI, Korn EL. Analyzing health surveys for cancer-related objectives. J Natl Cancer Inst 1999: 91: 1005
1016.
9. Hoffmann D, Djordjevic MV, Hoffmann I. The changing
cigarette. Prevent Med 1997: 26: 427434.
10. Howell TH, Ridker PM, Ajani UA, Hennekens CH, Christen
WG. Periodontal disease and risk of subsequent cardiovascular disease in U.S. male physicians. J Am Coll Cardiol
2001: 37: 445450.

58

11. Hujoel PP, Drangsholt M, Spiekerman C, DeRouen TA.

Periodontal disease and coronary heart disease risk. J Am
Med Assoc 2000: 284: 14061410.
12. Hujoel PP, Drangsholt M, Spiekerman C, De Rouen TA.
Examining the link between coronary heart disease and
the elimination of chronic dental infections. J Am Dent
Assoc 2001: 132: 883889.
13. Hujoel PP, Does chronic periodontitis cause coronary
heart disease? J Am Dent Assoc 2002: 133: 315365.
14. Hujoel PP, Drangsholt M, Spiekerman C, DeRouen TA. Preexisting cardiovascular disease and periodontitis: a followup study. J Dent Res 2002: 81: 186191.
15. Hyman J, Winn D. Cigarette smoking, periodontal disease
and heart attack history (Abstract). Ann Periodontol 2001:
6: 221.
16. Janket SJ, Baird A, Chuang SK, Jones JA. Heart of the matter. J Am Dent Assoc 2001: 132: 16481650.
17. Joshipura KJ, Rimm EB, Douglass CW, Trichopoulos D, Ascherio A, Willett WC. Poor oral health and coronary heart
disease. J Dent Res 1996: 75: 16311636.
18. Kronmal RA. Spurious correlation and the fallacy of the
ratio standard revisited. J Roy Stat Soc A Sta: 156: 379392.
19. Mattila KJ, Valtonen VV, Nieminen M, Huttunen JK. Dental
infection and the risk of new coronary events: prospective
study of patients with documented coronary artery disease. Clin Infect Dis 1995: 20: 588592.
20. Mazzaglia G, Britton AR, Altmann DR, Chenet L. Exploring
the relationship between alcohol consumption and nonfatal or fatal stroke: a systematic review. Addiction 2001:
96: 17431756.
21. McCullagh P, Nelder JA. Generalized Linear Models. Monographs on Statistics and Applied Probability no. 37, 2nd
edn.. London, New York: Chapman & Hall, 1989: xix, 511.
22. Morrison HI, Ellison LF, Taylor GW. Periodontal disease
and risk of fatal coronary heart and cerebrovascular diseases. J Cardiovasc Risk 1999: 6: 711.
23. Patrick DL, Cheadle A, Thompson DC, Diehr P, Koepsell T,
Kinne S. The validity of self-reported smoking: a review
and meta-analysis. Am J Public Health 1994: 84: 1086
1093.
24. Peto J. Cancer epidemiology in the last century and the
next decade. Nature 2001: 411: 390395.
25. Peto J. Obesity link to cancer. BBC Access date: May 7,
2002, http://news.bbc.co.uk/hi/english/health/newsid_
1334000/1334311.stm.
26. Saito T, Shimazaki Y, Sakamoto M. Obesity and periodontitis [letter]. N Engl J Med 1998: 339: 482483.
27. Spiekerman C, Hujoel PP, Drangsholt MT, Derouen TA. Inadequate adjustment for smoking in periodontitis systemic disease associations. (Abstract) Ann Periodontol
2001: 6: 221.
28. Thom DH, Grayston JT, Siscovick DS, Wang SP, Weiss NS,
Daling JR. Association of prior infection with Chlamydia
pneumoniae and angiographically demonstrated coronary
artery disease. J Am Med Assoc 1992: 268: 6872.
29. Wagenknecht LE, Burke GL, Perkins LL, Haley NJ,
Friedman GD. Misclassification of smoking status in the
CARDIA study. a comparison of self-report with serum cotinine levels. Am J Public Health 1992: 82: 3336.
30. Williamson DF. The prevention of obesity. N Engl J Med
1999: 341: 11401141.
31. Wu T, Trevisan M, Genco RJ, Dorn JP, Falkner KL, Sempos
CT. Periodontal disease and risk of cerebrovascular dis-

Periodontitis, systemic diseases and smoking

ease. The first national health and nutrition examination
survey and its follow-up study. Arch Intern Med 2000: 160:
27492755.

Appendix
Statistical adjustment: over-, under-, and
appropriate adjustment for confounders and its
relationship to divergent results on the
periodontitisstroke association
An analysis is said to be under-adjusted when an important
confounding variable such as alcohol, which is causing
both periodontitis and stroke, is inadequately accounted
for in the analyses. Under-adjustment may be a common
problem in periodontitissystemic disease studies and may
result in an over-estimation of the true association between
periodontitis and systemic diseases (27). In contrast, an
analysis is said to be over-adjusted when adjustment is
made for a potentially confounding variable that is in the
etiological pathway. For instance, if periodontitis causes increased serum C-reactive protein (CRP) levels, and high
CRP causes systemic disease, adjustment for CRP leads to
over-adjustment. As a result of this over-adjustment, the
true impact of periodontitis on systemic disease is underestimated. While no analysis is perfectly adjusted (all
models are wrong), the ideal analyses would make the
comparison of stroke in individuals with and without periodontitis identical with respect to all confounding variables
except the periodontal status.
The impact of over- vs. under-adjustment on the reported risks depends on the population under study. If individuals with and without periodontitis are similar with
respect to potentially confounding variables, over- vs.
under- adjustment will have almost no impact on the periodontitissystemic disease association. For instance, in the
Physicians Health Study, severe under-adjustment (no adjustment for any potentially confounding variables) leads
to the conclusion that periodontitis increases the risk for
a nonfatal myocardial infarction (MI) by 12% (10). When
adjustment is made for a long list of confounding variables
in the analyses (age, aspirin- and b-carotene-assignment,
smoking, alcohol use, hypertension, body mass index, diabetes, physical activity and family history of heart disease),
periodontitis is associated with a 1% increased nonfatal MI
risk. In this homogeneous population, the difference between under-adjusted vs. potentially over-adjusted analyses is small (11%). In homogeneous populations the topic
of potential over- vs. under-adjustment is primarily of academic interest only, because either approach leads to almost identical conclusions. On the other hand, if individuals with and without periodontitis are dissimilar with respect to potentially confounding variables, over- vs. underadjustment can lead to different conclusions.
In heterogeneous populations, different research groups
can obtain different answers depending on how confounding variables are adjusted for in the analyses. We report in this study that the risk for stroke associated with
periodontitis is an insignificant hazard ratio of 1.09. Another study using the same data reported a significant

32. Wynder EL, Muscat JE. The changing epidemiology of

smoking and lung cancer histology. Environ Health Perspect 1995: 103 (Suppl. 8): 143148.

stroke hazard ratio of 1.66 (31). For those individuals that

attach importance to P-values, these differences appear significant. This difference is likely to attract attention, it is
therefore important to understand why the differences occur and how this may relate to over- vs. under-adjustment.
The manner in which sampling weights, edentulous individuals, and alcohol use are handled in the analysis provides one illustration of how estimates regarding stroke can
vary depending upon how the analytical models are specified.

Sampling weights
Adjustment for sampling weights in the NHEFS sample
substantially increases periodontitissystemic disease associations. For stroke, the hazard ratio increases from 1.09
to 1.35. Because we do not understand how sampling
weights relate to the causal pathway and because no information is available on how sample weights were calculated,
we have presented both weighted and unweighted results
in all our work (11, 14). Statisticians working on the topic
of sampling weights have often elected to present the unweighted results (2, 8). In Table 1 of this report, unweighted
results are presented. Whether adjustment for sampling
weights is appropriate and represents over- or under-adjustment needs careful attention in periodontitissystemic
disease research because it influences the findings greatly.
Until information exists on how weights were calculated or
how they play a role in the causal pathway, we feel uncomfortable including them in our primary analyses.

Edentulous individuals
The inclusion of edentulous individuals inflates the periodontitissystemic disease associations. For stroke, the
hazard ratio changes from 1.09 to 1.15 (in the unweighted
analysis) or to 1.41 (in the weighted analyses). When the
primary goal of the analysis is to compare individuals with
periodontitis to individuals without gingivitis or periodontitis, the inclusion of edentulous individuals serves
only one purpose obtaining a more accurate estimate of
the impact of confounders. If such increased precision occurs at the cost of increased bias, it violates the principle
of first looking for a valid (unbiased) estimate, and only
then looking for ways to improve precision. Since the inclusion of edentulous individuals biases the comparison of
individuals with a healthy periodontium to individuals with
periodontitis, we believe that they should be deleted from
the analyses. For some diseases, such as lung cancer, the
inflation of the hazard ratio that results as a consequence
of including edentulous individuals is substantial.

Alcohol
A systematic review indicated the presence of a consistent
association between alcohol and stroke, with some evi-

59

Hujoel et al.
dence for a linear association between alcohol and hemorrhagic stroke, and inconsistent information for establishing
a J-shaped association for alcohol and ischemic stroke (20).
As a result, adjustment for the number of alcoholic drinks
is important. In an analysis that adjusts for the typical
number of drinks per week, the risk for periodontitis associated with stroke is 1.09. If one adjusts for alcohol consumption by including an indicator variable that is positive
when an individual reports yes to the question During the
past year have you had at least one drink of beer, wine, or
liquor? the hazard ratio increases to 1.17. Not adjusting
for number of drinks leads to a higher periodontitisstroke
association. Since individuals with periodontitis drink significantly more alcohol than individuals with a healthy
periodontium, not adjusting for alcohol is an under-adjustment, which spuriously inflates the periodontitisstroke association.
These various analyses show how hazard ratios can
change significantly depending on how statistical adjustments are made. Including edentulous individuals, not including an estimate of alcohol consumption, and including
sampling weights provides one example of how the hazard
ratio can be changed from an insignificant 1.09 to a significant 1.53.
An analysis plan (i.e. which variables to adjust for in the
analysis) should be decided prior to conduct of the analysis, rather than in response to what is seen in the data, in
order to avoid data dredging (i.e. searching for the analysis

60

that maximizes the desired result). For reporting stroke results, we utilized our analysis plan for coronary heart disease (CHD), which we adopted prior to analyzing the CHD
data. We did not see any reason to change this plan for
stroke because CHD and stroke have similar risk factors.
Rigorous control for confounding variables through restriction of the sample to, for example, never-smokers or to
those individuals for whom alcohol consumption is known,
comes at a cost a decreased sample size. In a study on
the effect of body mass index and mortality, the decision
to limit the primary analysis to healthy never-smokers resulted in an elimination of 75% of the sample (3). Valid
(unbiased) estimates for periodontitissystemic disease associations come at a similar price a substantial decrease
in precision. In the NHEFS study, our analyses resulted in
the elimination of individuals who did not provide information on the number of alcoholic drinks consumed or
smoking duration and dose. To limit the analyses to neversmokers with no prior history of cardiovascular disease,
54% of the NHEFS sample would be eliminated. While this
price in terms of deleted sample size is high, it may be the
best approach available for obtaining valid estimates. It is
of critical importance that these differences in analytic
plans and their corresponding differences in estimated effects be fully understood because very few large well-controlled cohort studies on the periodontitissystemic disease
associations are available.