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3
Methodologic Considerations in Evaluating the Evidence
THE NATURE OF THE EVIDENCE
The committee has undertaken the task of judging whether each of
a set of adverse events may occur as a result of exposure to
pertussis or rubella vaccines. These judgments have both
quantitative and qualitative aspects, and they reflect the evidence
examined and the approach taken to evaluate it. In this chapter,
the committee describes more fully how it has approached its task,
in the hope that readers may then be in a better position to assess
and interpret the committee's findings. By offering this
information, the committee wishes to make the report useful to
those who may seek to update its conclusions as new information is
obtained. This chapter outlines the specific questions the
committee posed, the types of evidence it identified, its
approaches to evaluating reports both singly and collectively, and
the nature of the conclusions it felt that logic and evidence
permitted. Against this background, details of the analysis and
specific conclusions concerning each type of adverse event appear
in subsequent chapters.
Attributes both of the adverse events being considered and of
the population exposed to vaccine influenced the committee's
analysis. The events can be characterized, for example, by their
frequency, discreteness, and specificity and by prior knowledge of
their etiology and pathogenesis. Events that occur only rarely in
exposed persons are more difficult to study than those that occur
more frequently. Conditions that are ill-defined, that are
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known to occur in the absence of vaccine exposure, or that
generally have unknown causes or mechanisms of development are also
inherently difficult to investigate. Under these circumstances,
epidemiologic studies offer important advantages over clinical
experience and intuition, although these limiting characteristics
affect epidemiologic studies also.
When the great majority of the population is exposed, as is
generally true for pertussis and rubella vaccines, comparisons
between exposed and nonexposed persons become clouded. This is due
to the potential for selective factors against vaccination to
confound the relation between immunization status and the
occurrence of adverse events. For example, a decreased relative
risk of SIDS has been observed in several studies in the time
period immediately following DPT immunization. Although a
protective effect of vaccine cannot be ruled out, it is more
plausible that children who are not immunized by the
recommended age are at increased risk for SIDS because of
other factors, such as socioeconomic status, that are associated
with both delaying immunization and SIDS (see Chapter 5). Other
aspects of vaccine exposure, such as changes in vaccine
formulation, single versus multiple occasions of administration,
and the age pattern of administration also bear on interpretation
of the evidence.
QUESTIONS TO BE ADDRESSED
What would it mean to say that a vaccine causes one or another
type of adverse event? It would not mean that exposure invariably
produces the adverse event, nor that all cases of the event were
due to the vaccine. Such complete correspondence between exposures
and events is by far the exception in public health and does not
occur in the present context, or the present review would not be
required.
In general matters of health and disease, different causal
explanations may apply even to a single disease. For example, the
question of what causes typical cases of a particular disease is
quite distinct from the question of what causes epidemic outbreaks
of that disease. The answers are also distinct, in that the first
might be a specific microorganism and exposure conditions of the
individual case, whereas the second could entail complex ecologic
and social factors suddenly favoring the widespread transmission of
the microorganism. Clearly, different senses of ''cause" are
implied in these two questions. Although each of these
questions concerns the causation of disease, the answers require
different types of evidence. This example suggests the importance
of stating clearly the questions about causation to be
answered.
In the present review, the committee has been concerned with
causal questions of three kinds. The first of these questions about
exposure to pertussis or rubella vaccine is, in general, can it
cause the specified adverse
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condition? For example, can rubella vaccine cause chronic
arthritis? If the conclusion is affirmative, a second question
becomes pertinent: How frequently does it cause that
condition? Or, how frequently is arthritis a result of rubella
vaccination? The third question, which applies to a particular
instance or case of an adverse event, is did it cause that
specific event? Or, did rubella vaccine cause this particular
individual to develop arthritis? Discussion of each of these three
types of questions will help to indicate the committee's view of
its task.
(1) Can vaccine cause the adverse
event?
While the nature of causation has a deep philosophical
underpinning, the work of the committee necessarily focused on a
pragmatic question: What is the nature of the evidence relevant to
drawing its conclusion about causation? In pursuing this question,
the committee recognized that an absolute conclusion about the
absence of causation may never be attained. As in science
generally, studies of adverse events following vaccination are not
capable of demonstrating a zero effect, that is, that the purported
effect is impossible or could not ever occur. Any instrument of
observation has a limit to its resolving power, and this is true as
well of randomized clinical trials and epidemiologic studies.
Hence, the committee could not prove the absence of any possibility
of an adverse event caused by vaccine. Rather, in the absence of
evidence suggesting an effect, and especially in the presence of
evidence not consistent with causation, the committee could only
conclude that the evidence fails to demonstrate an effect.
The evidentiary base that the committee found to be most helpful
derived from epidemiologic studies of populations. Here, the
primary question is whether an association exists between the
exposure (immunization) and the event. To determine whether an
association exists, epidemiologists estimate the magnitude of an
appropriate quantitative measure (such as the relative risk or the
odds ratio1) that describes the
joint occurrence of exposures and events in defined populations or
groups. Values of relative risk greater than 1 may indicate a
positive, or direct (harmful), association and are emphasized in
this discussion; values between 1 and 0 may indicate a negative, or
inverse (protective), association. The observed relative risk in
the study population must be sufficiently distant from unity to
meet a stated criterion of significance before an association is
said to be apparent.
1 Usage of
"relative risk," "odds ratio," or "estimate of relative risk" is
not consistent in the literature reviewed and cited in this report.
In its own usage, the committee intends that ''relative risk" be
used to refer to the results of cohort studies and "estimates of
relative risk" or "odds ratio" be used to refer to the results of
case-comparison studies (see Glossary of Terms for
definitions).
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Formally, in planning an investigation, an epidemiologist poses
a hypothesis to the effect that the exposures and events under
study are independent, or not associated. Under this hypothesis,
the value of the measure of association used is theoretically
expected to be approximately 1. This is termed the null
hypothesis or the hypothesis of no association. The measure of
association derived from the investigation is then tested
statistically. To "reject the null hypothesis," or to conclude that
exposures and events are not independent, is to conclude that there
is evidence of an association.
When more than one epidemiologic study has been conducted, it
may be instructive to combine their results so as to reach a
stronger conclusion than a single study can provide. This process
is described more fully later in this chapter.
Determining whether an observed association is causal requires
additional scrutiny. This is because there may be alternative
explanations for an observed association. These include errors in
the design, conduct, or analysis of the investigation; bias, or a
systematic tendency to distort the measure of association from
representing the true relation between exposures and events;
confounding, or distortion of the measure of association because
another factor, related to both exposures and events, has not been
recognized or taken into account in the analysis; and chance, the
effect of random variation in producing observations that can, in
reality, only be approximations to the truth and can, with some
probability, sometimes depart widely from the truth.
In deciding whether vaccine can cause any particular type of
event, then, it has been the committee's task to judge in each
instance whether there is evidence of association from the
available studies, and if so, whether it is direct or inverse, and
whether it is due to error, bias, confounding, or chance or,
instead, due to a causal relation between vaccine and event.
(2) How frequently does vaccine cause
the event?
The second type of causal question, which becomes pertinent only
if the answer to the first question is affirmative, concerns the
proportion of individuals in a specified population who experience
the adverse event because of the exposure. The most desirable
evidence as a basis for answering this type of question involves
knowledge of the rate of occurrence of the event in those who are
exposed, the rate in those who are not exposed (the "background"
rate of the event in the population), and the degree to which any
other differences between exposed and unexposed persons influence
the difference in rates. The term attributable risk is
generally used to denote the difference in rates between exposed
and unexposed groups. This is a simple measure of the frequency
with which the occurrence of the event in exposed persons may be
due to the vaccine exposure and not to the other
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causes that account for the event in the absence of vaccine
exposure (see Glossary of Terms). By also taking into account the
frequency of exposure in the population, a further measure can be
calculated which indicates the number of cases in a total
population that may be due to the exposure.
When information was available, in the presence of an
association judged by the committee to be causal, the committee has
attempted to indicate how much of the occurrence of the event in
question might be caused by vaccine exposure.
(3) Did vaccination cause a particular
case of the adverse event?
A third type of causal question is whether, in a specific
instance of exposure and an adverse event, it can be concluded that
the event was caused by the vaccine exposure. This question is
especially pertinent to those types of adverse events for which
case reports constitute a substantial part of the evidence
available for review. Three different sets of circumstances
bear on the nature of this question. First, it may have been judged
in general that the exposure can cause this type of event. In this
instance the question concerning any particular case needs to
consider the similarity between the circumstances of that case and
the circumstances in which the general conclusion was reached that
such causation can occur. If other causes of the same type of
event are known, their possible role in this individual case must
be considered also.
Second, most evidence for a general proposition of causation may
be negative, yet circumstances surrounding a single case may raise
the question of whether causation may be attributed to the exposure
of this individual. To judge that a particular case was caused by
the exposure under these circumstances would entail the reversal of
the more general conclusion on the basis of a single case. It seems
extremely unlikely that such a reversal could be justified on the
basis of the evidence concerning an individual case.
Third, there may be no evidence of the sort required to judge
the presence or absence of association. Here the judgment in a
specific case would depend on the circumstances concerning that
case alone, in isolation from any conclusion about a causal
relation in general. On consideration of several aspects of the
evaluation of case reports, discussed in the section below, even
the strongest affirmative answer based on the individual case would
be inherently weaker, or less securely supported, than it would be
if a general conclusion supporting vaccination as a cause of the
event had been reached. This is not to say that any such conclusion
reached on the basis of the case report alone is necessarily
incorrect. However, it would be highly subject to error in light of
the properties of most of the events considered here and the nature
of the evidence available about them in the case report.
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Representative terms from entire chapter:
adverse event
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THE BURDEN OF PROOF
In approaching its task, the committee considered the concept of
"burden of proof' and its place in such an evaluation. This concept
implies that one position or another concerning causation is
presumed to be true unless it is offset by evidence to the
contrary. The prior position might be either affirmative or
negative. That is, it may be assumed that an exposure is harmful
unless sufficient evidence of safety is present; alternatively, it
may be assumed that an exposure is safe unless convincing evidence
of harmful effects is present. In either case, it is sometimes
argued that a burden of proof must be fulfilled before the presumed
position is rejected.
In general, it is desirable to avoid making an error in either
direction, concluding either that there is or that there is not a
causal relation when the opposite is true. Reducing the chance of
such mistaken conclusions depends on careful assessment of the
evidence, including consideration of possible errors, bias, and
confounding.
The role of chance in leading to erroneous conclusions as a
result of random variation in sampling or in other respects is
customarily handled through formal statistical analyses, which are
based on assumptions from probability theory. Statistical measures
can suggest the likelihood that conclusions of the presence or
absence of association will each be in error. In general, a result
is said to have greater statistical significance as the probability
of error in accepting an association becomes smaller.2The
likelihood that a true association will be correctly detected in an
investigation is a statistical property of the investigation,
termed its power. Both statistical significance and power
reflect the role of chance in scientific observations and the
concomitant uncertainty in all scientific conclusions. One obvious
implication of this understanding is that the concept of "proof" in
its common-sense meaning is not strictly applicable to scientific
observations. Even when scientists conclude that an experiment
demonstrates ("proves") causation, they know there is a small,
statistically definable probability that the conclusion is
incorrect.
The committee began its evaluation presuming neither the
existence nor the absence of association. It has sought to
characterize and weigh the strengths and limitations of the
available evidence. Subsequent chapters of the report summarize the
evidence concerning each vaccine-event relation under review and
present the committee's conclusions. If the first question (can the
vaccine cause the adverse event?) was answered affirmatively,
and
2 More
technically, the level of statistical significance is the
probability of observing by chance at least as great a difference
as that observed between an "experimental" (exposed) and a
"control" (unexposed) group, if the risk of the adverse event were,
in truth, identical in the two groups.
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if available information permitted, the second question (how
frequently does the vaccine cause the adverse event?) was answered.
In a few cases, conclusions based on the answer to the third
question (did the vaccine cause the adverse event in this
individual case?) are proposed (see, for example, the section on
hemolytic anemia in Chapter 6). Of necessity, such a conclusion is
especially tentative if the more general question of whether the
vaccine can cause the adverse event remains unanswered.
Furthermore, the committee's task was not to judge individual
cases, except when this was the only way to shed light on the
general question of causality.
It should be noted that the committee's charge was to focus on
questions of causation and not broader topics, such as cost-benefit
or risk-benefit analyses of vaccination, which are not considered
in this report. With this orientation to the committee's task and
approach in mind, the following sections discuss the
characteristics of the types of evidence that bear on the causal
questions at hand.
CATEGORIES OF EVIDENCE
Experiments in Humans
Randomized Controlled Trials
Theoretically, the ideal method for assessment of causal
relations between treatments and adverse events is the randomized
controlled trial because, when appropriate and feasible, it is the
most scientifically rigorous method for testing such hypotheses.
Randomized controlled trials are experiments in which subjects are
randomly allocated, often in a masked fashion, into "treatment" and
"control" groups, to receive or not to receive an intervention such
as, in the present context, a monovalent vaccine; the control group
receives an injection of an inert substance (placebo) or an
established alternative vaccine; and both groups are followed up in
a strictly comparable manner to determine the relative frequencies
of outcomes and events of interest.
Although they are theoretically ideal, such trials have ethical
and practical limitations for investigating the causal connections
of concern here. Widespread acceptance of routine immunization
against pertussis and rubella creates ethical barriers to
withholding vaccination from some participants to permit a
placebo-controlled trial (Cherry et al., 1988). In addition,
because these adverse events are generally rare, the sample sizes
required to detect them reliably would be much larger than those
required to evaluate vaccine efficacy. In fact, since the first
reports of serious adverse events following administration of
pertussis and rubella vaccines (Madsen, 1933; Modlin et al., 1975),
virtually no placebo-controlled or other experimental
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studies in humans of the adverse events covered in this report
have been published (Cherry et al., 1988; Plotkin, 1988; Preblud,
1985).
A number of early studies of pertussis vaccine in the United
States and the United Kingdom did include unexposed controls, but
these studies were primarily concerned with efficacy and not with
adverse events (e.g., Kendrick and Eldering, 1939; Lapin, 1943;
Medical Research Council, 1951, 1956, 1959). More recently, a small
number of studies have compared adverse reaction rates in children
following DPT versus DT vaccine administration (Cody et al., 1981;
Pollock et al., 1984) or in adults following rubella vaccine versus
natural rubella infection (Tingle et al., 1986). Predominantly,
however, pertinent randomized trials have focused on comparisons of
pertussis vaccine reaction rates between different injection sites,
vaccines of different manufacturers, prior reaction histories, or
different immunization schedules (Baraff et al., 1984, 1985; Barkin
and Pichichero, 1979). Other studies have compared reaction rates
by vaccine type, for example, whole-cell versus acellular pertussis
vaccines (e.g., Edwards et al., 1986; Lewis et al., 1986;
Pichichero et al., 1987) or between rubella vaccine strains (e.g.,
Barnes et al., 1972; Isacson et al., 1971; Polk et al., 1982). In
general, these studies have been primarily concerned with
evaluation of transient reactions, whether local or systemic, and
not chronic adverse events of the types included in this review.
One exception is a randomized, double-masked, placebo-controlled
trial of rubella vaccine and chronic arthritis that is currently in
progress in Vancouver, British Columbia, Canada. Results are
expected in 1992 (A. Tingle, British Columbia Children's Hospital,
personal communication, 1991).
Other Experimental Studies
Thus, few randomized controlled trials contribute to the
assessment of the causal questions considered in this report. And
although it should be noted for completeness that other
experimental approaches, such as formal communitywide comparisons
of the impact of vaccination programs, including both beneficial
outcomes and adverse events, are applicable in principle, evidence
of this type is also generally unavailable.
Experiments in Animals: Animal
Models
In principle, experimental studies in animals allow for both
rigid control over vaccine exposure and intensive observation for
any adverse events that may follow. If an animal model is to be
considered valid for the study of a human disease, however, the
manifestations of the disease should be similar in the two species.
The starting point is generally what is currently known about the
human disease.
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With respect to evaluation of pertussis vaccine, the committee
found that the information gained from animal models of whooping
cough is difficult to apply to humans for two critical reasons:
Knowledge of virulence factors for the organism and of the
pathogenesis of whooping cough is incomplete and largely
superficial, and Bordetella pertussis is not a natural
pathogen for animals. Nonetheless, several studies have been
conducted and are reviewed below. With respect to rubella, the
committee could find no studies of animal models of either the
disease or rubella vaccine-related illness that were specific to
the adverse events under consideration. The discussion below
therefore refers specifically to pertussis.
Several additional factors make it difficult to apply findings
in animal models of infection to their human counterparts, and
these difficulties hold for the study of pertussis. These factors
are either specific characteristics of infection and response in a
particular species or more general considerations in judging the
relevance to humans of studies in animals.
First, the capacity of any particular organism to infect (i.e.,
to colonize and replicate in) a host varies a great deal across
host species. This variability depends in turn on several factors,
including how closely the organism's surface antigens resemble
those of the host. If the microbe's prominent antigens are like
those of the host, rapid replication might occur before the host
would recognize the invader as foreign. Some organisms initiate
their relationship with the host by binding to specific host
receptors or antigens; these binding sites vary among species. An
animal's immunologic repertoire, consisting of antibodies and
programmed lymphocytes, is generated by natural exposure to
antigens. Across species this experience with antigens varies with
diet and habitat, particularly proximity to humans or other
animals.
Second, disease is the product of a stimulus (such as a
bacterium and its toxins) and the host response. The inflammatory
response is similar but far from identical across mammalian
species, and the disease can be expressed differently in different
species. For example, different animals vary in their capacity to
inactivate bacterial endotoxin and in their susceptibility to
allergic anaphylaxis.
Third, results in animal models of infectious diseases can vary
greatly with the conditions of the initial exposure of the host to
the organism. If animal models of infection involve the same point
of entry, the same vehicle (e.g., dust or aerosolized droplets),
and similar numbers of organisms in order to produce natural
infection, they are more likely than less analogous models to
predict the results that will be obtained in humans.
Fourth, the material used for studies in animals (in this case,
the organism and its products) should, ideally, be the same as that
to which the human is exposed. Attention must be paid to the
bacterial strain and to possible differences in metabolism and
virulence within the strain.
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Fifth, host defense mechanisms mature at markedly different
rates in different species. The stage of immunologic development in
the test animal needs to be understood in relation to development
of the immune system in the human.
Results with animal models can only suggest possible relations
or outcomes in humans. Observations made in animal models represent
only an initial step in the process of applying animal experience
to human disease and its prevention. Findings from the animal model
must be confirmed by the study of humans, and that principle is
clearly relevant to the study of either whooping cough or the
adverse events that follow pertussis vaccination. With respect to
the study of adverse events following exposure to rubella or
rubella vaccine, such questions of relevance are moot, since it has
not been possible to develop an animal model for rubella
infection.
These general requirements for the applicability of data from
animal models to human conditions limit the usefulness of the
information currently available regarding pertussis vaccine. No
pertinent information is available from animal models regarding
rubella vaccine. Observational studies in humans have been a more
useful basis for making judgments about the possibility of
causation of adverse events by pertussis and rubella vaccines. (See
Appendix C for further discussion of the animal models used to
study pertussis and pertussis vaccine.)
Controlled Epidemiologic Studies
(Observational)
In contrast to randomized controlled trials and other
experimental studies in humans, many epidemiologic investigations
are observational. This means simply that the occurrences of
exposures or events of concern, such as pertussis vaccination or a
particular adverse event, are studied as they arise in the usual
course of life and not under the conditions of a planned
experiment.
Observational studies in populations are often controlled,
however, through various strategies of formal comparative
investigation. For example, the experience of adverse events in a
group after receiving pertussis vaccine can be compared with that
in an unvaccinated group (unexposed control group). Alternatively,
the prior vaccination history of a group that has developed
irreversible encephalopathy can be compared with that of a group
free of this condition (unaffected control group). In these two
strategies, the experience of the control or comparison group
provides an estimate of the frequency either of events in the
absence of exposure or of exposure in the absence of the event, as
experienced in the general population. Thus, the contribution of
the control group in such studies is analogous to that of the
placebo group in a controlled trial.
The most relevant types of such controlled, observational
studies for the
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present review and their main characteristics are described in
this section. Examples of studies related to pertussis or rubella
vaccine and adverse events serve for illustration.
Cohort Studies
Cohort studies track groups that are defined by common
characteristics, including their exposure status, for example,
vaccinated and unvaccinated, at the starting point of observation.
The rates of occurrence of adverse events are compared between
these groups over time. All study participants are known or
presumed to be free of the disease or events under investigation at
the start of the study. In the well-designed cohort study, reliable
estimates of event rates in each group can be obtained.
Especially for uncommon events, large populations, prolonged
periods of observation, or both are required (Last, 1988).
Such studies can provide evidence that bears on both the first
and second types of causal questions discussed earlier in this
chapter. By direct comparison of rates in exposed versus nonexposed
groups, a measure of association, termed the relative risk,
is derived. From the same results, the attributable risk can be
determined, and with knowledge of the frequency of exposure in the
general population, the population attributable risk can also be
calculated. Thus, the questions of whether exposure is associated
with the event and, if so, to what degree can both be answered with
the results of the cohort study.
The starting point of the investigation can be either
contemporaneous or in the past. In the first case, termed
concurrent cohort studies, all observations, including both
exposures and events, may be subject to direct observation by the
investigator. In the second case, which typically depends on the
availability of records of past exposures and events, the entire
study may relate to experience prior to the start of the
investigation. Such studies are termed historical cohort
studies. Some features are common to both types of cohort
studies, and others are distinct in accordance with their different
temporal strategies.
For example, in a historical cohort study, Griffin and
colleagues (1990) evaluated the risks of seizures and
encephalopathy in a cohort of 38,171 children in Tennessee on
Medicaid who had collectively received a standard schedule of
107,154 DPT immunizations in the first 3 years of life (see Chapter
4 for details). The use of historical records permitted a more
rapid and less expensive investigation than would have been
afforded by a concurrent cohort design.
One potential weakness of the historical cohort study design,
the dependence on possibly incomplete and unreliable historical
records for information, was reduced in the study of Griffin and
colleagues because of the
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recognized, however, that perfect specificity could not be
expected given the multifactorial etiology of many of the adverse
events under examination.
Biologic Plausibility Biologic plausibility is
based on whether a possible causal association fits existing
biologic or medical knowledge. The existence of a possible
mechanism, such as an established association of the adverse event
with natural disease (e.g., thrombocytopenic purpura following
natural rubella infection), was thought to increase the likelihood
that the vaccine-event association could be causal.
Other Considerations As noted above, it is
important also to consider whether alternative
explanations—error, bias, confounding, or chance—might
account for the finding of an association. If an association could
be sufficiently explained by one or more of these considerations,
there would be no need to invoke the several considerations listed
above. From this viewpoint, an inference of causation could be
based solely on the exclusion of these alternatives. Because
these alternative explanations can rarely be excluded sufficiently,
however, assessment of the applicable considerations listed above
almost invariably remains. The final judgment is then a balance
between the strength of support for the causal interpretation and
the degree of exclusion of alternatives.
Other considerations were also entertained in the evaluation of
the evidence of association. One special consideration in
evaluating summary evidence on the relation of adverse events to
pertussis or rubella immunization was that of the variation in
vaccine composition observed across manufacturers.
With respect to the whole-cell pertussis vaccine, for example,
the committee recognized that methods of production, seed bacteria,
preservatives, and adjuvants used in manufacturing the vaccine have
varied substantially over the years (Cox et al., 1987; Ross, 1988)
and vary even now by manufacturer and country. In some countries,
such as the United States, adsorbed vaccines are used exclusively.
In others, both plain (fluid) and adsorbed vaccines are available,
and in some, only plain vaccines are available. In most countries,
pertussis immunization is given in conjunction with diphtheria and
tetanus toxoids in a combined DPT product. In countries where
inactivated polio vaccine is used, a quadruple antigen (diphtheria,
tetanus, pertussis, and polio) vaccine is used. In yet other
countries, pertussis vaccine is given primarily as a monovalent
vaccine.
The committee also recognized that pertussis immunization
schedules have varied markedly by country and time period. In the
United States, for example, DPT vaccine is currently administered
in five doses at ages 2, 4, 6, and 18 months and 4 to 6 years
(American Academy of Pediatrics, 1988).
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In The Netherlands, DPT-polio vaccine is given in four doses at
ages 3, 4, 5, and 11 to 14 months (Health Council of The
Netherlands, 1987). Rubella-containing vaccines, like pertussis
vaccine, have also varied considerably across place and time. For
example, three vaccine strains were used initially in the United
States following licensure in 1969-1970: HPV-77 (duck embryo),
HPV-77 (dog kidney), and Cendehill (rabbit kidney) (Hilleman et
al., 1969; Meyer et al., 1969; Prinzie et al., 1969). Soon after,
the RA 27/3 human diploid fibroblast vaccine was licensed in Europe
(Plotkin et al., 1969), and both the HPV-77 (dog kidney) and the
Cendehill vaccines were subsequently withdrawn from U.S. licensure.
In 1979, RA 27/3 was licensed in the United States, and the HPV-77
(duck embryo) vaccine was withdrawn, leaving RA 27/3 as the only
U.S.-licensed rubella vaccine (Perkins, 1985).
In addition to strain variations, rubella-containing vaccines
also vary in composition. In the United States, and increasingly
elsewhere, rubella vaccines are combined in a triple vaccine also
containing measles and mumps vaccine viruses (MMR). However,
bivalent vaccines containing rubella and measles or rubella and
mumps vaccines are also used.
What, then, are the implications of these variations in vaccine
composition and schedules for the evaluation of vaccine-adverse
event associations? With respect to rubella vaccines, rates of
arthritis and arthralgia following immunization were found to
differ by strain (see Chapter 7). Integration of evidence across
studies was therefore problematic. This issue was considered moot
with respect to radiculoneuritis and other neuropathies and
thrombocytopenic purpura, since the evidence for these adverse
events was limited to isolated case reports.
Unlike rubella vaccines, however, the committee considered the
potential problem of variability in whole-cell pertussis vaccine
composition to be much greater. For example, in the last 10 years
of testing of pertussis vaccines at the National Institute for
Biological Standards and Control (NIBSC) in the United Kingdom,
whole-cell vaccines have shown wide variation in biologic activity
from batch to batch, although with no significant time-related
trends (K. Redhead, National Institute for Biological Standards and
Control, personal communication, 1990). Testing did reveal that
plain pertussis vaccines are usually more active than adsorbed
vaccines, a finding consistent with studies cited in the report
(e.g., Pollock et al., 1984) which indicate that the frequency of
moderate systemic reactions following primary immunization with
adsorbed DPT vaccine is similar to that with adsorbed DT vaccine,
but considerably less than that with plain DPT vaccine.
In summary, the general approach to evaluation outlined in this
chapter was applied to each type of adverse event as dictated by
the nature of the available evidence.
Page 56
THE NATURE OF THE CONCLUSIONS
This chapter has demonstrated that judgments about the possible
causation of adverse events by pertussis or rubella vaccine and
similar causal questions reflect both quantitative and qualitative
reasoning. Some final observations will help to clarify the nature
of the committee's conclusions.
Quantitation
Resolution
Resolution refers to the fineness or sharpness of detail that
can be discriminated by a particular mode of observation. In light
microscopy, for example, observations are described by reference to
the optical properties of the lens, such as 10x, 100x, or higher
magnification. Electron microscopy, with very much higher
resolution, distinguishes structural features not detectable with
light microscopy.
Resolution in epidemiologic studies concerns the capacity of a
study to discriminate between the frequencies of events or of
exposures between groups in order to determine the presence or
absence of associations. By analogy, resolution in epidemiology
also depends in a sense on magnification, that is, on the order of
magnitude of the numbers of participants—for example, from
tens to hundreds of cases and controls in case-comparison studies
and from hundreds to thousands of exposed and unexposed subjects in
cohort studies. With equally valid observations, results based on
the experience of increasing numbers of persons, from single
individuals to tens, hundreds, or thousands of individuals, provide
successively greater resolution.
The resolution or discriminating capacity of epidemiologic
studies could theoretically be increased indefinitely through ever
larger study populations. However, there are many constraints on
the feasibility of large studies. Rarity of exposures or events or
other circumstances may limit the resolution even of large studies.
Meta-analysis can, under the appropriate circumstances discussed
above, be used to offset the limited size of individual studies,
but the collective magnitude of the contributing studies may still
be less than desired. It should be emphasized that in all such
studies the potential for bias is a key problem and that enlarging
the study only reduces random error, not systematic error.
Therefore, if bias is present, a firmer but still erroneous
conclusion will result from a larger study than from a smaller
one.
Power calculations indicate the probability of achieving
discrimination of a predetermined degree under the design of a
given study. Power is thus a quantitative measure of the capacity
of a study to achieve a given degree
Page 57
of resolution. In particular, it provides guidance against
overconfidence in the absence of an association when a study with
relatively low power has failed to demonstrate one. As such, it is
an aid in appreciating the nature of the evidence that underlies
conclusions about causation and is described further here to
indicate its role in the present review.
As discussed earlier in this chapter, two types of error must be
taken into account in designing and interpreting statistical tests.
Epidemiologic studies are often designed to provide statistical
tests that minimize type I error, the probability that the
null hypothesis is falsely rejected. Commonly, such tests are
designed so that there is less than a 5 percent chance that the
test will incorrectly indicate an association between a vaccine and
an adverse event if no association truly exists. For any given test
and sample size, on the other hand, there is some chance that the
test will err in failing to find an association when one truly
exists. This is called a type II error. The chance of making
such an error increases when both the true excess risk and the
sample size are small. From another perspective, given a particular
sample size and a specified probability of a type I error, one can
calculate the power of a test to detect an assumed association of a
given magnitude. Because the power of a test is the opposite
(technically, the complement) of the probability of making a type
II error, the power of a test increases when both the true excess
risk and the sample size are large.
For example, Shields and colleagues (Melchior, 1977; Shields et
al., 1988) compared the ages of onset of various disorders under
different vaccination schedules in two time periods in Denmark and
found no statistically significant differences between the two
periods in the onset of infantile spasms. However, there were only
80 cases of infantile spasms in the two study periods combined, and
the lack of a significant statistical association may therefore
reflect the small sample size rather than a true absence of
association. In other words, if this investigation were replicated
in a country with more cases of infantile spasms than occurred in
Denmark, a statistically significant difference might be detected,
if the relation was, in truth, causal.
Furthermore, according to the power calculations described in
Appendix D, if 50 percent of cases of infantile spasms were caused
by pertussis vaccine, there would be nearly a 90 percent chance
that a sample of the size used by Shields and colleagues would
detect this relationship. If, on the other hand, only 25 percent of
the cases of infantile spasms were caused by pertussis vaccine,
Shields and colleagues' test has about a 45 percent chance of
detecting the relationship.
Power calculations are also valuable in interpreting apparently
conflicting results of multiple studies of the same vaccine-adverse
event combination. If findings of no association were concentrated
in the low-power studies, for instance, the suggestion that no
association exists would be weakened.
Page 58
Because power calculations help to illuminate an important
aspect of the uncertainty in the evidence it evaluated, the
committee decided to calculate, whenever possible, the power of the
statistical tests on which its conclusions were based. These
calculations are described in Appendix D.
Uncertainty and Confidence
All science, including the spectrum from particle physics to
astrophysics, is characterized by uncertainty. Scientific
conclusions concerning the result of a particular analysis or set
of analyses can range from highly uncertain to highly confident. As
discussed earlier in this chapter, the theoretical concept of proof
does not apply in evaluating actual observations. In its review,
the committee attempted to assess the degree of uncertainty
associated with the results on which it had to base its
conclusions.
For individual studies, confidence intervals around estimated
results such as relative risks represent a quantitative measure of
uncertainty. Confidence intervals present a range of results that,
with a predetermined level of probability, include the true
relative risk being estimated. When it is possible to use
meta-analysis to combine the results of different studies, a
combined estimate of the relative risk and confidence interval may
be obtained. Appendix D describes the methods used for
meta-analysis in the report.
For an overall judgment about causation based on a whole body of
evidence, beyond the results of single studies or of meta-analyses,
no quantitative method exists for characterizing the uncertainty of
the conclusions. Thus, to assess the appropriate level of
confidence to be placed on the ultimate causal conclusions, it may
be useful to consider qualitative as well as quantitative
aspects.
Quality
Comprehensiveness
An important aspect of the quality of a review such as the
present one is comprehensiveness. This is to ensure against the
possibility of any serious omission or inappropriate exclusion of
evidence from consideration. If any such omission should be
identified, a determination would be needed of whether its
inclusion would likely affect the overall results and, if so, in
what way.
In this report the committee has documented in detail its
approach to seeking and identifying the evidence to be reviewed
(see Appendix A, Strategies for Gathering Information). Numerous
parties were invited to supplement the materials already under
review and to notify the committee of any recognized omissions of
importance.
Page 59
Neutrality
Neutrality is another important consideration in the quality of
such conclusions as those presented by the committee. This is to
ensure a fair weighing of all of the evidence. In this connection,
the committee avoided the posture of the burden of proof approach,
as discussed earlier in this chapter. The essential evidence, its
main strengths and limitations, and the conclusions that follow are
stated for each adverse event considered.
Judgment
The evaluation of evidence to reach conclusions about causation
goes beyond quantitative procedures, at several stages: assessing
the relevance and validity of individual reports; deciding on the
possible influence of error, bias, or confounding on the reported
results; integrating the overall evidence, within and across
diverse areas of research; and formulating the conclusions
themselves. These aspects of the review required thoughtful
consideration of alternative approaches at several points. They
could not be accomplished by adherence to a prescribed formula.
Rather, the approach described here evolved throughout the
process of the review and was determined in important respects by
the nature of the evidence, exposures, and events at issue.
Both the quantitative and the qualitative aspects of the process
that could be made explicit were important to the overall review.
Ultimately, the conclusions expressed in this report about
causation are based on the committee's collective judgment. The
committee endeavored to express its judgments as clearly and
precisely as the available data allowed.
SUMMARY OF THE EVIDENCE
Table 3-1 summarizes the types of evidence reviewed for each
adverse event and the respective contribution of each to the
committee's judgments about causation. The evidence is organized
under five headings: (1) human experiments; (2) animal experiments;
(3) case-comparison, cohort, and other controlled studies, (4) case
reports and case series; and (5) biologic plausibility. The first
four categories were discussed earlier in this chapter. The fifth
category, biologic plausibility, includes background knowledge
concerning the pathophysiology of an adverse event, attributes of a
particular vaccine, or other biologic information derived from
research in such areas as immunology and physiology.
Where evidence was available in a particular category, the
committee judged whether that evidence was generally supportive or
not supportive of causation or whether it was insufficient for a
determination. For example,
Page 60
TABLE 3-1 Categories of Evidence Reviewed
for Each Adverse Event: Is the Evidence Supportive of
Causation?a
Vaccine and Adverse Event
Human Experiments
Animal Experiments
Case-Comparison,
Cohort, and Other Controlled Studies
Case Reports
and Case Series
Biologic Plausibility
(Chapter of Report)
Yesb
?c
Nod
Yes
?
No
Yes
?
No
Yes
?
No
Yes
?
No
DPT
Infantile spasms (4)
X
X
Hypsarrhythmia (4)
X
X
Aseptic meningitis (4)
X
X
Acute encephalopathye (4)
X
X
X
X
Chronic neurologic damage (4)
X
X
X
X
Sudden infant death syndrome (5)
X
X
Anaphylaxis (6)
X
X
X
X
Autism (6)
Erythema multiforme or other rash (6)
X
X
Guillain-Barrè syndrome (polyneuropathy)
(6)
X
Peripheral mononeuropathy (6)
X
Hemolytic anemia (6)
X
X
Page 61
Vaccine and Adverse Event
Human Experiments
Animal Experiments
Case-Comparison,
Cohort, and Other Controlled Studies
Case Reports
and Case Series
Biologic Plausibility
(Chapter of Report)
Yesb
?c
Nod
Yes
?
No
Yes
?
No
Yes
?
No
Yes
?
No
Juvenile diabetes (6)
X
X
X
Learning disabilities and hyperactivity (6)
X
X
Protracted inconsolable crying and screaming
(6)
X
X
X
Reye syndrome (6)
X
X
Shock and ''unusual shocklike state" (6)
X
X
Thrombocytopenia (6
X
RA 27/3 Rubella
Arthritis (7)
Acute
X
X
X
X
Chronic
X
X
X
Radiculoneuritis and other neuropathies (7)
X
X
Thrombocytopenic purpura (7)
X
X
a Blanks for any
given category of evidence indicate that evidence of this kind is
lacking.
b Yes,
Evidence of this kind is supportive of causation.
c ?, Evidence of
this kind cannot be classified either as supportive or as not
supportive of causation.
d No, Evidence of
this kind is not supportive of causation.
e Defined in
controlled studies reviewed as encephalopathy, encephalitis, or
encephalomyelitis.
Page 62
where there were relevant controlled studies which, overall, had
relative risks of greater than 1, the evidence was classified as
"supportive of causation." Blanks for any given category of
evidence indicate that evidence of that type was lacking. It
is important to note that any one category of evidence generally
was not sufficient in itself to support a conclusion of causality,
since other aspects of the evidence, including the number and
quality of contributing studies, the details of results obtained,
and other considerations outlined earlier in this chapter all
weighed into the committee's evaluation.
The committee found it convenient to classify its conclusions
about each adverse event under one of five categories, reflecting
the strength and direction of its conclusions. These categories
are:
1. No evidence bearing on a causal relation
2. Evidence insufficient to indicate a causal
relation
3. Evidence does not indicate a causal relation
4. Evidence is consistent with a causal relation
5. Evidence indicates a causal relation.
The remaining chapters elaborate on the evidence
assembled as the basis of the committee's findings and
conclusions.
REFERENCES
Alderslade R, Bellman MH, Rawson NSB, Ross
EM, Miller DL. 1981. The National Childhood Encephalopathy Study: a
report on 1000 cases of serious neurological disorders in infants
and young children from the NCES research team. In: Whooping Cough:
Reports from the Committee on the Safety of Medicines and the Joint
Committee on Vaccination and Immunisation. Department of Health and
Social Security. London: Her Majesty's Stationery Office.
American Academy of Pediatrics. 1988. The
Red Book. Report of the Committee on Infectious Diseases, 21st
edition. Peter G, ed. Elk Grove, IL: American Academy of
Pediatrics.
Baraff LJ, Cody CL, Cherry JD. 1984.
DTP-associated reactions: an analysis by injection site, prior
reactions, and dose. Pediatrics 73:31-36.
Baraff LJ, Cherry JD, Cody CL, Marcy SM,
Manclark CR. 1985. DTP vaccine reactions: effect of prior reactions
on rate of subsequent reactions. Developments in Biological
Standardization 61:423-428.
Barkin RM, Pichichero ME. 1979.
Diphtheria-pertussis-tetanus vaccine: reactogenicity of commercial
products. Pediatrics 63:256-260.
Barnes EK, Altman R. Austin SM, Dougherty
WJ. 1972. Joint reactions in children vaccinated against rubella.
Study II: comparison of three vaccines. American Journal of
Epidemiology 95:59-66.
Berg JM. 1958. Neurological complications
of pertussis immunization. British Medical Journal 2:24-27.
Byers RK, Moll FC. 1948. Encephalopathies
following prophylactic pertussis vaccination. Pediatrics
1:437-457.
Centers for Disease Control. 1984. Adverse
Events Following Immunization: Surveillance
Page 63
Report No.1, 1979-1982. Atlanta: Public
Health Service, U.S. Department of Health and Human Services.
Centers for Disease Control. 1986. Adverse
Events Following Immunization: Surveillance Report No.2, 1982-1984.
Atlanta: Public Health Service, U.S. Department of Health and Human
Services.
Centers for Disease Control. 1989. Adverse
Events Following Immunization: Surveillance Report No.3, 1985-1986.
Atlanta: Public Health Service, U.S. Department of Health and Human
Services.
Centers for Disease Control. 1990. Vaccine
adverse event reporting system—United States. Morbidity and
Mortality Weekly Report 39:730-733.
Cherry JD, Brunell PA, Golden GS, Karzon
DT. 1988. Report of the task force on pertussis and pertussis
immunization—1988. Pediatrics 81(6, part 21):939-984.
Cody CL, Baraff LJ, Cherry JD, Marcy SM,
Manclark CR. 1981. Nature and rates of adverse reactions associated
with DTP and DT immunizations in infants and children. Pediatrics
68:650-660.
Corsellis JAN, Janota I, Marshall AK.
1983. Immunization against whooping cough: a neuropathological
review. Neuropathology and Applied Neurobiology 9:261-270.
Coulter HL, Fisher BL. 1985. DPT: A Shot
in the Dark. New York: Harcourt Brace Jovanovich.
Cox NH, Morley WN, Forsythe A. 1987.
Vaccine reactions and thiomersal. British Medical Journal
294:250.
Edwards KM, Lawrence E, Wright PF. 1986.
Diphtheria, tetanus, and pertussis vaccine: a comparison of the
immune response and adverse reactions to conventional and acellular
pertussis components. American Journal of Diseases of Children
140:867-871.
Griffin MR, Ray WA, Mortimer EA, Fenichel
GM, Schaffner W. 1990. Risk of seizures and encephalopathy after
immunization with the diphtheria-tetanus-pertussis vaccine. Journal
of the American Medical Association 263:1641-1645.
Health Council of The Netherlands. 1987.
Adverse Reactions to Vaccines in the National Vaccination Programme
in 1986. The Hague, The Netherlands: Gezondheidsraad.
Hill AB. 1971. Principles of Medical
Statistics, 9th edition. New York: Oxford University Press.
Hilleman MR, Buynak EV, Whitman JE, Weibel
RD, Stokes J. 1969. Live attenuated rubella virus vaccines:
experiences with duck embryo cell preparations. American Journal of
Diseases of Children 118:166-171.
Isacson P, Kehrer AF, Wilson H, Williams
S. 1971. Comparative study of live, attenuated rubella virus
vaccines during the immediate puerperium. Obstetrics and Gynecology
37:332-337.
Kendrick PL, Eldering G. 1939. A study in
active immunization against pertussis. American Journal of Hygiene
29:133-153.
Kleinbaum DG, Kupper LL, Morgenstern H.
1982. Epidemiologic Research: Principles and Quantitative Methods.
Belmont, CA: Lifetime Learning Publications.
Lapin JH. 1943. Whooping Cough.
Springfield, IL: Charles C Thomas.
Last JM, ed. 1988. A Dictionary of
Epidemiology, 2nd edition. New York: Oxford University Press.
Lewis K, Cherry JD, Holroyd HJ, Baker LR,
Dudenhoeffer FE, Robinson RG. 1986. A doubleblind study comparing
an acellular pertussis-component DTP vaccine with a whole-cell
pertussis-component DTP vaccine in 18-month old children. American
Journal of Diseases of Children 140:872-876.
Madsen T. 1933. Vaccination against
whooping cough. Journal of the American Medical Association
101:187-188.
Martin GI, Weintraub MI. 1973. Brachial
neuritis and seventh nerve palsy: a rare hazard of DPT vaccination.
Clinical Pediatrics 12:506-507.
Page 64
Mausner JS, Kramer S. 1985. Epidemiology:
An Introductory Text, 2nd edition. Philadelphia: W.B. Saunders
Co.
Medical Research Council. 1951. The
prevention of whooping cough by vaccination. British Medical
Journal 1:1463-1471.
Medical Research Council. 1956.
Vaccination against whooping cough: relation between protection in
children and results of laboratory tests. British Medical Journal
2:454-462.
Medical Research Council. 1959.
Vaccination against whooping cough: the final report. British
Medical Journal 1:994-1000.
Melchior JC. 1977. Infantile spasms and
early immunization against whooping cough. Danish survey from 1970
to 1975. Archives of Disease in Childhood 52:134-137.
Meyer HM, Parkman PD, Hobbins TE, Larson
HE, Davis WJ, Simsarian JP, Hopps HE. 1969. Attenuated rubella
viruses: laboratory and clinical characteristics. American Journal
of Diseases of Children 118:155-165.
Modlin JF, Brandling-Bennett AD, Witte JJ,
Campbell CC, Meyers JD. 1975. A review of five years' experience
with rubella vaccine in the United States. Pediatrics 55:20-29.
Perkins FT. 1985. Licensed vaccines.
Reviews of Infectious Diseases 7:S73-S76.
Pichichero ME, Badgett JT, Rodgers GC,
McLinn S, Trevino-Scatterday B, Nelson JD. 1987. Acellular
pertussis vaccine: immunogenicity and safety of an acellular
pertussis vs. a whole cell pertussis vaccine combined with
diphtheria and tetanus toxoids as a booster in 18- to 24-month old
children. Pediatric Infectious Disease Journal 6:352-363.
Plotkin SA. 1988. Rubella vaccine. In:
Plotkin SA, Mortimer EA, eds. Vaccines. Philadelphia: W.B. Saunders
Co.
Plotkin SA, Farquhar JD, Katz M, Buser F.
1969. Attenuation of RA27/3 rubella virus in WI38 human diploid
cells. American Journal of Diseases of Children 118: 178-185.
Polk BF, Modlin JF, White JA, DeGirolami
PC. 1982. A controlled comparison of joint reactions among women
receiving one of two rubella vaccines. American Journal of
Epidemiology 115:19-25.
Pollock TM, Miller E, Mortimer JY, Smith
G. 1984. Symptoms after primary immunisation with DTP and with DT
vaccine. Lancet 2:146-149.
Preblud SR. 1985. Some current issues
relating to rubella vaccine. Journal of the American Medical
Association 254:253-256.
Prinzie A, Huygelen C, Gold J, Farquhar J,
McKee J. 1969. Experimental live attenuated rubella virus vaccine:
clinical evaluation of Cendehill strain. American Journal of
Diseases of Children 118:172-177.
Ross EM. 1988. Reactions to whole-cell
pertussis vaccines. In: Wardlaw AC, Parton R, eds. Pathogenesis and
Immunity in Pertussis. New York: John Wiley & Sons.
Rothman KJ. 1986. Modern Epidemiology.
Boston: Little, Brown & Co.
Shields WD, Nielsen C, Buch D, Jacobsen V,
Christenson P, Zachau-Christiansen B, Cherry JD. 1988. Relationship
of pertussis immunization to the onset of neurologic disorders: a
retrospective epidemiologic study. Journal of Pediatrics
113:801-805.
Tingle AJ, Ford DK, Price GE, Kettyls DWG.
1979. Prolonged arthritis in identical twins after rubella
immunization (brief report). Annals of Internal Medicine
90:203-204.
Tingle AJ, Chantler JK, Pot KH, Paty DW,
Ford DK. 1985. Postpartum rubella immunization: association with
development of prolonged arthritis, neurological sequelae, and
chronic rubella viremia. Journal of Infectious Diseases
152:606-612.
Tingle AJ, Allen M, Petty RE, Kettyls GD,
Chantler JK. 1986. Rubella-associated arthritis. I. Comparative
study of joint manifestations associated with natural rubella
infection and RA 27/3 rubella immunisation. Annals of the Rheumatic
Diseases 45:110-114.