Vaccine
Safety > Research
Confounding in Studies of
Adverse Reactions to Vaccines
As published in American Journal of Epidemiology, July 15, 1992; 136(2):
121-135
Authors: |
Paul E M Fine, VMD, PhD
Robert T Chen, MD, MA
Centers for Disease Control and Prevention
National Immunization Program
1600 Clifton Road, MS E-61
Atlanta, Georgia 30333
|
Abstract
Several social and medical attributes are associated both with avoidance
or delay of vaccination and an increased risk of adverse events such as sudden infant
death syndrome (SIDS) or childhood encephalopathy. Studies that fail to control adequately
for such confounding factors are likely to underestimate the risks of adverse events
attributable to vaccination. This paper reviews the literature on studies of severe
adverse events after the administration of pertussis antigen-containing vaccines, with
particular attention to the measures taken by different investigators to avoid this
problem. Most published studies have reported a deficit of SIDS among vaccinees, which may
reflect confounding in their study designs. An expression is derived to explore the extent
of underestimation that may be introduced in such studies, under different sets of
conditions. Confounding of this sort is a general problem for studies of adverse reactions
to prophylactic interventions, as they may be withheld from some individuals precisely
because they are already at high risk of the adverse event.
Introduction
Immunization programs are undeniably among the most effective public
health interventions. Reductions over recent decades in the morbidity and mortality
attributable to smallpox, measles, polio, diphtheria, whooping cough, and tetanus are
eloquent reminders of this fact (1). However, the very success of these programs brings
new problems. No intervention is entirely without risk, and even very rare adverse
reactions to a vaccination increase in importance as the target disease itself disappears.
Changes in the perception of risks attributable to vaccination, compared
with those attributable to natural disease, are of immense importance to vaccination
programs. Recognition of these changes within the scientific community led to termination
of smallpox vaccination in many countries prior the global elimination of disease. Such
recognition also is now the basis for reconsideration of polio vaccination
strategies (2,3). The public perception of such changes led to dramatic declines in the
uptake of pertussis vaccination during the 1970's in the United Kingdom and Japan (4,5).
Similar concerns in the United States have led to a large number of lawsuits, a
substantial rise in vaccine prices (6), and new legislation governing reporting and
compensation of adverse events (7). Given such issues, one sees an obvious need for
continued monitoring of vaccine safety to assist policymakers in assessing needs for
improvements in vaccine preparations or for changes in vaccination strategy.
The monitoring of vaccine safety may be based on either active or passive
ascertainment of adverse events (8). To assess whether such events are in fact
attributable to vaccination, the investigator may use two sorts of approach. The first
involves cohort logic, i.e., the comparison of incidence rates of the event in question
between cohorts of vaccinated and unvaccinated individuals. If there are very few
unvaccinated individuals in the population, then the comparison may be between
(age-specific) rates of events before and at successive intervals after vaccination. The
alternative approach involves the application of case-control logic, i.e., comparisons of
the frequency of a history of recent vaccination between individuals experiencing adverse
events and appropriate controls.
Regardless of the approach used, such studies face several methodological
difficulties (9-10). Many potential sources of bias have been identified. Prominent among
these is the problem of ensuring that adverse events are ascertained independently of
vaccination history. Failure to control for this factor may lead to creation, or
overestimation, of an association between a vaccine and an adverse event. Another problem
is that of confounding between the risk factor (vaccination) and outcome measure (adverse
event) of interest. Many factors known to be associated with either avoidance or delay of
vaccination may themselves be associated with an increased risk of adverse event-type
medical outcomes. As an illustration, Table 1 presents reported risk factors for sudden
infant death syndrome (SIDS) and for childhood encephalopathy, on the one hand, and for
failure to receive diphtheria-tetanus-pertussis (DPT) vaccination on the other (11-22).
The close correspondence between these sets of factors, which include medical
contraindications and social correlates of low vaccine coverage, suggests that individuals
predisposed either to SIDS or to encephalopathy are relatively unlikely to receive DPT
vaccination. Studies that do not control adequately for this form of "confounding by
indication" (23) will tend to underestimate any real risks associated with
vaccination.
This paper examines the influence of such confounding on vaccine adverse
event studies by reviewing the literature to illustrate its presence and by modeling to
demonstrate its impact under different sets of conditions.
Review of the Literature
Published studies that are relevant to the problem of confounding between
risk factors for DPT vaccination and for potential adverse events are summarized in Table
2. This review does not cover reports of cases or clusters of time-associated adverse
events (24-25), as these are not likely to be representative and they provide no means to
evaluate the confounding problem that is the focus of this paper.
Studies of DPT and SIDS
The first published controlled investigation of the relation between DPT
and SIDS was a case-control study by Taylor and Emery in 1982 (26), who reported that 8
(31%) of 26 SIDS cases had ever received DPT or DT vaccine compared with 27 (52%) of 52
age- and area- matched controls (odds ratio= 0.41). Except for the matching of controls,
no attempt was made to overcome confounding by factors predisposing to vaccination or to
SIDS in this investigation.
The following year, Baraff et al. (27) reported data on the time interval
between DPT vaccination and death of 27 SIDS cases who had received DPT vaccine within 28
days prior to death. A significant excess of deaths was noted within 24 hours (observed =
6; expected = 0.96; p < 0.005) and within 7 days (observed = 17; expected = 7.72; p
< 0.05) of vaccination. Subsequent correspondence discussed the potential for
selection, recall, and observer bias in this study and raised the possibility that the
association might have been due in part to the similarity in age trends between SIDS
incidence and DPT vaccination (28). The paper also included an analysis of intervals
between visits to physicians and death for 40 SIDS cases reported to have sought medical
care (but not received vaccination) within 28 days prior to death. There was an excess of
visits within 7 days, which may have reflected prodromal symptoms associated with the
subsequent deaths of these children. Given that some of these symptoms may have been
interpreted as contraindications to vaccination, we again see evidence of the concordance
of risk factors summarized in Table 1.
Results of the largest investigation of the relation between DPT and SIDS
were reported by Hoffman et al. in 1987 (14). These were based upon a multicenter
case-control study comparing risk factors in 757 SIDS cases with those in randomly
selected living controls matched for birthplace and age (control group A) or for
birthplace, age, race and birth weight (control group B). Overall, SIDS cases were less
likely to have received DPT (or any vaccine) than were their matched controls (odds
ratios= 0.54 [control group A] and 0.58 [control group B]). The significant negative
association between prior DPT vaccination and SIDS was maintained in multiple logistic
analysis controlling for 11 other factors: birthweight, sex, race, parity, maternal age,
maternal education, smoking during pregnancy, alcohol consumption during pregnancy, use of
prenatal care, prepregnancy weigh, and pregnancy weight. Case children were less likely
than controls to have had postnatal outpatient visits, but more likely to have had sick
visits; but no attempt was made, however, to control for these factors in the analyses.
The negative association between vaccination and SIDS was strongest when analyses were
restricted to vaccination within 24 hours of death (crude odds ratios= 0.19 [control group
A] or 0.46 [control group B]). The authors concluded, "DPT immunization does
not appear to be a significant factor in the occurrence of SIDS." (14, p. 610).
A smaller case-control study based on linked data was reported by Walker
et al. (29). These authors compared 29 SIDS cases with 262 age-matched controls drawn from
linked vaccination and mortality records of 26,500 children registered between 1972 and
1983 with the Group Health Cooperative of Puget Sound. SIDS was defined as "...any
death for which no cause could be discerned among infants of normal birthweight (> 2500
grams) and without predisposing medical conditions...." (29, p. 245). The criteria
for "predisposing medical conditions" were not stipulated in detail, but led to
the exclusion of two children with "life-threatening medical conditions" (29,
p.950). Such exclusions represent an effort to control for confounding in the design of
this study, and should have compensated to some degree for the concordance of risk factors
illustrated in Table 1. These authors found a negative association between SIDS and a
history of having ever received DPT (odds ratio = 0.15). On the other hand, when
nonimmunized children are excluded from analysis, detailed breakdown by successive
intervals between DPT vaccination and death suggested that the daily mortality risk in the
period 0 to 3 days after vaccination (4 deaths observed) was 7.5 (95% CI: 1.7 - 31) times
greater than that during the period more than 30 days after vaccination (9 deaths
observed).
Griffin et al. (30) linked birth, death and immunization records in
Tennessee in order to follow up 129,834 infants who were born over the years 1974 - 1984
and recorded as having received at least one dose of DPT vaccine. Sudden infant death was
reported in 109 of these children between the ages of 29 days and 1 year of life. Cohort
logic was used in order to calculate the relative risks of SIDS in successive intervals
after receipt of DPT vaccine, compared to the risk of SIDS occurring more than 30 days
after vaccination. A clear gradient in relative risk was observed, from a low of 0.2
during the first 72 hours after vaccination to unity for the period 2 weeks or more after
vaccination. The trend remained when controlled for age, sex, race, year, birth weight,
and Medicaid enrollment. The authors interpreted the finding as follows: "The most
plausible explanation for the decreased rate of SIDS in the period immediately after
immunization is that children may be immunized when they are in better health and that
this healthier state is associated with a lower risk of SIDS." (30, p.621). The
authors then attempted to evaluate the potential impact of such confounding on their
investigation, noting that other studies had shown that "nearly half of all children
who die of SIDS have either no symptoms or very minor ones before death. Therefore these
studies suggest that selective immunization of asymptomatic cohort children could at most
account for a 50% decrease in the rate of SIDS after immunization in this study, but that
the decrease could not be of sufficient magnitude to mask a true increase in the incidence
of SIDS after immunization." (30, p. 622).
This statement implies two things. First, even if more than half of
the children who died of SIDS had prior symptoms that might have rendered them ineligible
for vaccination shortly before death, such selection "could" still only have
reduced the observed relative risk by a maximum of 50%, at least under the conditions of
their study. Second, their finding of a relative risk of 0.18 (see Table 2) was
therefore incompatible with a true relative risk greater than unity. We will return
to the logic of this argument below.
In summary, we see that all investigators have found that SIDS
cases are less likely to have ever been vaccinated than are living age-matched
controls. On the other hand, analyses of time intervals between DPT vaccination and SIDS
have shown a deficit of deaths shortly after vaccination in some studies
(14,26,30) and an excess of such deaths in others (27, 29) The two positive
short-interval associations were based upon small numbers (27 and 29 total cases), and may
have been due in part to the fact that the peak age distribution of SIDS coincides with
the recommended onset of DPT vaccination. This was exacerbated by the use of time more
than 30 days after vaccination as the reference period, as this extends into ages of low
background risk.
All in all, the negative associations between DPT vaccination and SIDS are
impressive. None of the investigators cited above has suggested that these findings might
be due to DPT being protective against SIDS, and several have noted that the findings are
probably attributable to the fact that risk factors for SIDS are similar to factors known
to be associated with either avoidance or delay of vaccination (e.g. Table 1). The
negative associations between SIDS and having ever been vaccinated reflect avoidance
of vaccination. On the other hand, the negative associations between SIDS and having recently
been vaccinated could reflect either avoidance or delay of vaccination
by those predisposed, for one reason or another, to die of SIDS.
Studies of DPT and
encephalopathy:
The British National Childhood Encephalopathy Study
(NCES) represents the
largest controlled study of encephalopathy and DPT vaccination thus far carried out. It
also includes the most thoughtful discussion in the literature on the issue of confounding
between factors predisposing both to avoidance of vaccination and the adverse reaction
under study (16, 31).
The NCES was designed as a case-control study comparing detailed
vaccination histories of more than 1000 encephalopathy cases with those of controls (2 per
case) matched for sex, date and area of birth. Significant associations were revealed
between encephalopathy and receipt of DPT vaccine less than 7 days before onset of illness
or between encephalopathy and receipt of measles vaccine within 7-14 days prior to onset
of illness, but no association was detected with prior DT vaccination. Many aspects
of this study, in particular, biases that may have been introduced by the method of case
ascertainment, have been discussed extensively in the literature (e.g., 10).
The authors explored the potential for confounding in four ways. First,
they restricted their most rigorous analyses to those cases who had no evidence of
neurological abnormality prior to onset of the encephalopathy. This should have controlled
for most neurological factors (except for febrile convulsions, which were not treated as
prior neurological abnormalities) that may have served as contraindications for
vaccination. Second, they carried out separate analyses excluding all cases and controls
with previous history of fits (again in an effort to control for factors that might have
influenced both the risk of encephalopathy and the propensity to be vaccinated). Third,
they carried out a separate analysis, matching for social class (manual v nonmanual
occupation of the head of the family). The significant association remained, leading the
authors to comment, "There is, therefore, no evidence that correcting for the
effect of social class eliminates or diminishes the significant association demonstrated
between serious neurological disorder and immunization against pertussis, or that social
class is a significant confounding variable." (16, p. 132) Finally, the authors
considered "other possible confounding variables...such...as past family and personal
medical history, and other environmental conditions. For these, or any other factor, to
cause significant bias in the calculations of relative risk they would need to operate
powerfully and consistently in one direction, to be specific for one vaccine (DPT) and not
another (DT), and to concentrate their influence on the observed associations over
relatively short time intervals before onset which differed between vaccines (DPT and
measles). It seems highly improbable that all of these criteria would be satisfied by any
of the confounding variables postulated in this Study." (16, p. 132).
The authors of the NCES study were concerned whether confounding factors
might have been responsible for creating the observed significant association between DPT
vaccination and encephalopathy. Given that all of the factors listed in Table 1 would be
expected to reduce rather that to create such an association, the
conclusion of the Study of a significant association between recent DPT vaccination and
encephalopathy does not appear to be threatened by any failure to control for additional
factors that relate both to the propensity for (avoidance of) vaccination and to the risk
of encephalopathy. Indeed, as might have been predicted, controlling for previous
neurological status, for prior history of fits, and social class led to increases
in the estimated relative risks, the only exception being in a subanalysis of one social
class group (manual), for which the estimated relative risks associated with DPT remained
virtually unchanged.
Three other investigations of the relation between between DPT vaccination
and encephalopathy or serious neurologic illness have now appeared. Both Walker et al (32)
and Griffin et al (33) have extended their studies of DPT and SIDS to include
encephalopathies. Neither found any evidence of an association with DPT vaccination, but
the numbers of cases were small and none had recently received DPT, which may reflect
avoidance of vaccination by children at risk. In addition, a preliminary report has
appeared, describing a major case-control study of acute, serious, neurological diseases
of children in Oregon and Washington states in the United States (34). Matched-set
analysis of the first 100 severe cases revealed an odds ratio of 2.5 (95% confidence
interval 0.7 - 9.3) with a history of DPT vaccination within the previous 7 days.
Adjustment for several factors that might be related to vaccine avoidance (personal or
family history of seizures, prior DPT reaction, and illness within 30 days) led to an
increase in the odds ratio to 3.6 (95% confidence interval 0.8 - 15.2), although the
relationship was still not statistically significant. Once again,
we see evidence of confounding and must ask whether the adjustment
actually carried out has removed the effects entirely.
Theoretical Argument
The extent of bias introduced by confounding will be a function of several
variables. In order to explore the quantitative implications of these variables, we begin
with the following definitions, using DPT and SIDS as an example.
S = Risk of SIDS in unvaccinated children who lack the
contraindication to vaccination. (It should be noted that we refer to
"contraindication" here to exemplify any factor associated with avoidance or
delay of vaccination.)
R = True relative risk of SIDS associated with vaccination.
D = Relative risk of SIDS associated with the contraindication.
C = Proportion of children with the contraindication.
V = Proportion vaccinated among children without the
contraindication.
P = Proportion vaccinated among children with the contraindication.
Using these definitions, we can calculate the expected risk of SIDS in
different segments of the child population, as shown in Table 4. It should be noted that
these predictions assume that the risks of SIDS associated with vaccination and with the
contraindication are independent and, thus, the risk of SIDS among children who are
vaccinated despite having the contraindication is R*D times that in unvaccinated children
who lack the contraindication. Given these expressions, we can estimate what would be the
observed relative risk of SIDS associated with vaccination, if an investigation were to
take no account of the potential confounding by contraindication (i.e., no appropriate
matching or stratification). With cohort logic, the observed relative risk would be
a(c+d)/c(a+b), using conventional definitions for the cells of Table 5. In a case-control
study, the odds ratio (ad/bc) should give a close approximation of the relative risk,
given that the adverse event is rare (i.e., a and c are small).
We explore the implications of these expressions under two general sets of
circumstances. The first relates to probabilities of vaccination and of SIDS such as would
accumulate over a year (analogous to studies that have used a history of having ever been
vaccinated as the risk factor). In this long term case, the (annual) risk of SIDS may be
on the order of S = 0.001 (35), and the overall proportion vaccinated at least once may be
on the order of V = 0.7 to 0.9. The second uses parameter levels such as might arise in
short-term studies which examine the risk of SIDS within one day or one week of
vaccination. In this case, the risk of SIDS will be small, on the order of S = 3*10-6
per day or 2*10-5 per week, and the probability of vaccination also small, on
the order of V = 0.01 per day or 0.7 per week.
Figures 1 and 2 present the ratios between the observed and the
"true" relative risks of SIDS, associated with vaccination, under each of these
circumstances, and given different sets of assumptions as to the values of the several
parameters. Although risk factors such as those listed in Table 1 are unlikely to be
associated with relative risks (D) greater than 10, D=30 is included for sensitivity
analysis to examine the impact of extreme values.
An interesting feature of this relation between observed and true relative
risks is its independence of R (the true relative risk) and of S (the background risk of
SIDS in the population). The magnitude of the bias is a function of the degree to which
the contraindications are observed (i.e., the ratio V/P), as this determines the
proportions with contraindications and, hence, the risks of adverse events in the
vaccinated and unvaccinated populations. The lower the proportion (P) vaccinated among
those with "contraindications" (i.e., the greater the extent to which
contraindications are observed by those responsible for vaccination), the greater will be
the bias in a study that does not control for these factors. Under both the long- or
short-term assumptions, we see that a substantial bias in estimating R can occur, given
levels of D greater than 10 and prevalences of the contraindication (C) greater than 1 %.
Table 6 illustrates the implications of various combinations of variables
for the observed relative risks of SIDS associated with the vaccination, as a function of
the true relative risks and the observed proportion of SIDS cases who have the
contraindication. We see that it is possible for the observed relative risk of SIDS
associated with vaccination to be less than half the true relative risk, even if half the
children with SIDS have contraindications.
Discussion
Review of the literatures on SIDS, encephalopathies and DPT suggests that
a large number of factors are associated both with a tendency to avoid or to delay
vaccination and an increased risk of SIDS and other serious neurological events (Table 1).
That failure to control for such factors may lead to spurious negative associations
between vaccination and adverse events is evident in several published investigations
(Table 2). Examination of the logic underlying this relation reveals that failure to
control for such factors in analyses may mask true associations between vaccinations and
certain adverse outcomes under certain conditions (Tables 3-6; Figures 1,2). In
particular, we note that the extent of relative risk underestimation will be related
directly to the proportion of individuals with contraindications to vaccination that are
also risk factors for the adverse outcome, the relative risk of the adverse outcome
associated with these contraindications, and the extent to which these contraindications
to vaccination are observed (i.e., the difference in vaccination coverage between
individuals with and without the contraindications).
The magnitude of such confounding effects may be considerable. The five
studies of DPT and SIDS summarized in Table 2 reported relative risk estimates ranging
from 0.15 to 5.4 using various methods; however, most of the estimates were below 1.0, and
four of the studies have reported at least some relative risk measures below 0.2 (Table
2). It seems unlikely to us, though, on biological grounds that the true relative risk in
this situation could be less than unity (as this would imply that such vaccines provide
some immediate non-specific protection against sudden infant death). Although the
underestimation may have been due in part to biased case ascertainment, inappropriate
control selection, or chance effects, its most obvious source is the confounding problem
discussed in this paper. Major reductions are seen when the prevalence of
contraindications exceeds 1%, and the effect approaches its maximum when their prevalence
reaches 5% (Figures 1 and 2). It may not be unreasonable to suppose that 5% of infants in
many populations will have at least one of the confounding risk factors cited in Table 1
(36,37).
In contrast to the conclusion of Griffin et al (30), our
simulations demonstrate that it is at least possible for the observed relative risk to be
less than half the true value even if more than half of the cases (e.g. of SIDS) have risk
factors for avoidance of vaccination (Table 6). On the other hand, our exploration
of parameter values, such as might arise in "recent vaccination history" studies
exemplified by Griffen et al., does not easily explain the very low relative risks of SIDS
associated with DPT vaccination observed by some investigators (14, 30). Sampling
errors aside, observed relative risks on the order of 0.2 could arise even if the true
relative risk were greater than 1.0, if one assumes that the contraindications were highly
prevalent (high C) and associated with a very high relative risk of the adverse outcome
(high D) (e.g., if V=0.01, C=0.2, D=50, and P=0.01, then a true relative risk of R=1.2
would be observed as 0.24). Such a high prevalence of so strong a
contraindication/risk factor, however, seems implausible. Risk factors such as those
listed in Table 1 are unlikely to be associated with relative risks (D) greater than 10,
let alone 30 or 50. Thus, whether the low observed relative risks of SIDS associated
with vaccination reflect sampling error, interactions among several contraindications/risk
factors, or other sorts of biases, or, indeed, whether they do reflect some
"protective" effect of vaccination remains unclear to us and awaits elucidation.
We note, however, that reanalysis of the British National Childhood Encephalopathy
Study of all cases and controls with any potential contraindications to vaccination has
led to a fourfold increase, from 3.3 to 12.6 (95% confidence interval 2.8-114.7), in the
estimated relative risk of encephalopathy subsequent to DPT vaccination (D. Miller, St.
Mary's Hospital Medical School, London, personal communication, 1990).
In theory, it might be possible to estimate the extent of this bias in a
particular situation, but this would require knowledge of the nature, frequency, and
implication of each of the six factors that may influence both propensity to be vaccinated
and the risk of adverse event (Table 3). The difficulty of obtaining such information on
all six factors makes it extremely hard to assess whether an observed relative risk of,
for example, 0.2 is consistent with a true relative risk greater than 1.0. This inference
is made even more problematic by the fact that many other sorts of bias, for example,
relating to case ascertainment, may influence the observed relative risk.
In reviewing the literature for this paper, we have been impressed that
much more is known about factors associated with a failure to receive adequate vaccination
in different societies than about the nature and the frequency of factors that lead to
postponement of vaccination. It may be expected that a number of situations (ill health on
the part of the child or other family member, domestic crises in the family) will lead
parents to delay taking their child to be vaccinated and that some of these situations
will themselves be risk factors for severe neurological episodes or SIDS. For example,
Stanton et al found that parents reported prior symptoms classified as
"major", i.e., "...usually needing a medical opinion on the same day and
continuing close supervision..." (38, p. 1250) in 48% of 145 SIDS cases as compared
to 12% of age-matched controls (odds ratio = 7). It is likely that most parents and health
care providers would postpone vaccination of children with such symptoms. Given that
studies of associations between vaccination and severe adverse reactions typically focus
on narrow time intervals between prior vaccination and onset of the "reaction",
it becomes important to understand the nature and frequency of vaccination-postponing
factors in study populations. This is an area of research that has attracted inadequate
attention in the past.
We have focused in this paper on just one of many methodological problems
confronting studies of adverse reactions to vaccinations. Most published discussions of
the subject have concentrated upon biases that act to overestimate the relative risk of
adverse events following vaccination (10). Biases that underestimate the risk, as
discussed here, have received less attention. The fact that such biases do exist makes it
difficult to demonstrate convincingly that a vaccine is not responsible for rare, severe,
adverse reactions. The avoidance of so many potential confounding factors presents a
difficult challenge to epidemiologists who would study the problem of rare, severe,
adverse reactions to vaccines. If such studies are to prove useful, they must include
strenuous efforts to control for such factors in their design, analysis and
interpretation. Whether this is possible at all may be open to discussion. The difficulty
of doing so is indisputable.
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