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36
Using Quality of Life Measurements in
Pharmacoepidemiology Research
GORDON H. GUYATT
Department of Medicine and Department of Clinical Epidemiology and Biostatistics, McMaster University,
Hamilton, Ontario, Canada
ROMAN JAESCHKE
Department of Medicine, St Joseph's Hospital, Hamilton, and Department of Medicine, McMaster University,
Hamilton, Ontario, Canada

INTRODUCTION These areas encompass the ability to function

One may judge the impact of drug interventions by
examining a variety of outcomes. In some situa-
tions, the most compelling evidence of drug
efficacy may be found as a reduction in mortality
normally; to be free of pain and physical, psycho-
logical, and social limitations or dysfunction; and to
be free from iatrogenic problems associated with
treatment. On occasion, the conclusion reached
when evaluating different outcomes may differ:
(-blockers after myocardial infarction), rate of
hospitalization (neuroleptic agents for schizophre-
nia), rate of disease occurrence (antihypertensives
for strokes), or rate of disease recurrence (some
form of chemotherapy after surgical cancer treat-
ment). Alternatively, clinicians frequently rely on
direct physiological measures of the severity of a
disease process and the way drugs influence these
measuresÐ for example, left ventricular ejection
fraction in congestive heart failure, spirometry in
chronic airflow limitation, or glycosylated hemo-
globin level in diabetes mellitus.
Clinical investigators have recognized that there
are other important aspects of the usefulness of the
interventions which these epidemiological, physio-
logical, or biochemical outcomes do not address.
Pharmacoepidemiology, Third Edition. Edited by B. L. Strom.
# 2000 John Wiley & Sons, Ltd.
physiological measurements may change without
people feeling better,1, 2 a drug may ameliorate
symptoms without a measurable change in physio-
logical function, or life prolongation may be
achieved at the expense of unacceptable pain and
suffering.3 The recognition of these patient oriented
(versus disease oriented) areas of well-being led to
the introduction of a technical term: health related
quality of life (HRQL).
Quality of life, as it is often used, lacks focus and
precision and, because it is an abstract concept, its
definition has led to much debate. Since the patient's
subjective well-being is influenced by many factors
unrelated to the disease process or treatment (i.e.,
education, income, quality of the environment, etc.),
investigators have adopted the narrower term,
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604 PHARMACOEPIDEMIOLOGY
HRQL. Some definitions of HRQL stem from the
recognition that HRQL may be considered on
different levels: an overall assessment of well-being;
several broad domainsÐphysiological, functional,
psychological, and social status; and subcomponents
of each domainÐfor example pain, sleep, activities
of daily living, sexual function within physical and
functional domains.
It follows that HRQL is a multifactorial concept
that, from the patient's perspective, represents the
final common pathway of all the physiological,
psychological, and social influences of the thera-
peutic process.4 It follows also that when assessing
the impact of a drug on patients' HRQL, one may
be interested in describing the patients' status (or
changes in the patients' status) on a whole variety of
domains, and that different strategies and instru-
ments are required to explore separate domains.
Definitions of HRQL, both theoretical and
practical, remain controversial. Most HRQL
measurement instruments focus largely on how
patients are functioning, e.g., their ability to care
for themselves and carry out their usual roles in
life. While this pragmatic view of HRQL has
gained ascendancy, there remain those who argue
that unless you are tapping into individual
patients' values you may be measuring health
status, but you are not measuring HRQL.5
These issues can be clarified by thinking of a
woman with quadriplegia who, despite her limita-
tions, is very happy and fulfilled and values her life
highly (more, for instance, than most people, or
than she did before she suffered quadriplegia). On
most domains of most HRQL instruments, this
woman's results would suggest a poor HRQL,
despite the high value she places on her health
state. Investigators and those interpreting the
results of HRQL measure should be aware of the
varying emphasis put on individual patient values
in the different types of instrument.6
CLINICAL PROBLEMS TO BE
ADDRESSED BY
PHARMACOEPIDEMIOLOGY RESEARCH
HRQL effects may be pertinent in both investigat-
ing and documenting beneficial as well as harmful
aspects of drug action. The knowledge of these
drug effects may be important, not only to the
regulatory agencies and physicians prescribing the
drugs, but to the people who are to take the
medication and live with both its beneficial actions
and side effects. Investigators must therefore
recognize the clinical situations where a drug
may have an important effect on HRQL. This
requires careful examination of data available
from earlier phases of drug testing and, until
now, has usually been performed in the latter
stages of phase III testing. For example, Croog
and colleagues studied the effect of three estab-
lished antihypertensive drugs Ðcaptopril, methyl-
dopa, and propranolol Ð on quality of life, long
after their introduction in clinical practice.7 Their
report, which showed an advantage of captopril in
several HRQL domains, had a major impact on
the drug prescription pattern at the time of its
publication. The earlier in the process of drug
development potential effects on quality of life are
recognized, the sooner appropriate data may be
collected and analyzed.
METHODOLOGIC PROBLEMS TO BE
ADDRESSED BY
PHARMACOEPIDEMIOLOGY RESEARCH
Researchers willing to accept the notion of the
importance of measuring HRQL in pharmacoepi-
demiology research and ready to use HRQL
instruments in postmarketing (or, in some cases,
premarketing) trials, face a considerable number
of challenges. These challenges start with the
realization that, as we have noted, there is no
universal agreement on what the concept of quality
of life actually entails. Thus, investigators must
define as precisely as possible the aspects of HRQL
in which they are interested.
Having identified the purpose for which a
HRQL instrument is to be used, one must be
aware of the measurement properties required for
it to fulfill its purpose. An additional problem
occurs at this stage if the original instrument was
developed in a different languageÐ the adequate
performance of an instrument cannot be assumed
after its translation. At the next step, the investi-
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USING QUALITY OF LIFE MEASUREMENTS IN PHARMACOEPIDEMIOLOGY RESEARCH
gator is challenged by the task of choosing from
many available HRQL measurement instruments.
When all these problems are dealt with satisfacto-
rily, the investigator has to ensure that the
measurements (interviews or self- or computer
administered questionnaires) are made in a rigor-
ous (standardized, reproducible, unbiased) fash-
ion. Finally, one is left with the chore of
interpreting the data and translating the results
into clinically meaningful terms.
CURRENTLY AVAILABLE SOLUTIONS
QUALITY OF LIFE MEASUREMENT
INSTRUMENTS IN INVESTIGATING NEW
DRUGS: POTENTIAL USE AND NECESSARY
ATTRIBUTES
In general terms, any HRQL instrument could be
used either to discriminate among patients (either
according to current function or according to
future prognosis), or to evaluate changes occurring
in the health status (including HRQL) over time.8, 9
In most clinical trials, quality of life measurement
instruments are used for evaluation of the effects
of therapy, with treatment effect being expressed
as a change in the score of the instrument over
time. Occasionally, instruments are used to dis-
criminate among patients. An example would be a
study evaluating the effect of drug treatment on
functional status in patients after myocardial
infarction, where the investigators may wish to
divide potential patients into those with moderate
versus poor function (with a view toward inter-
vening in the latter group).
The purpose for which an instrument is used
dictates, to some degree, its necessary attributes.
Each HRQL measurement instrument, regardless
of its particular use, should be valid. The validity
of an instrument refers to its ability to measure
what it is supposed to measure. This attribute of a
measurement instrument is difficult to establish
when there is no gold standard, as is the case with
evaluation of HRQL. In such situations, where so
called criterion validity cannot be established, the
validity of an instrument is frequently established
605
in a stepwise process including examination of face
validity (or sensibility)10 and construct validity.
Sensibility relies on an intuitive assessment of
the extent to which an instrument meets a number
of criteria including applicability, clarity and
simplicity, likelihood of bias, comprehensiveness,
and whether redundant items have been included.
Construct validity refers to the extent to which
results from a given instrument relate to other
measures in a manner consistent with theoretical
hypotheses. For example, one could hypothesize
that changes in spirometry related to a use of a
new drug in patients with chronic airflow limita-
tion should bear a close correlation with changes
in functional status of the patient and a weaker
correlation with changes in their emotional status.
The second attribute of an HRQL instrument is
its ability to detect the ``signal,'' over and above
the ``noise'' is introduced in the measurement
process. For discriminative instruments, those that
measure differences among people at a single point
in time, this ``signal'' comes from differences
between patients in HRQL. In this context, the
way of quantitating the signal-to-noise ratio is
called reliability. If the variability in scores
between subjects (the signal) is much greater than
the variability within subjects (the noise), an
instrument will be deemed reliable. Reliable
instruments will generally demonstrate that stable
subjects show more or less the same results on
repeated administration. The reliability coefficient
(in general most appropriately an intraclass
correlation coefficient) measuring the ratio of
between subject variance to total variance (which
includes both between and within subject variance)
is the statistic most frequently used to measure
signal-to-noise ratio for discriminative instru-
ments.
For evaluative instruments, those designed to
measure changes within individuals over time, the
``signal'' comes from the differences in HRQL
within patients associated with the intervention.
The way of determining the signal-to-noise ratio is
called responsiveness and refers to an instrument's
ability to detect change. If a treatment results in an
important difference in HRQL, investigators wish
to be confident they will detect that difference,
even if it is small. The responsiveness of an
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606 PHARMACOEPIDEMIOLOGY
instrument is directly related to (i) the magnitude
of the difference in score in patients who have
improved or deteriorated (the capacity to measure
this signal can be called changeability), and (ii) the
extent to which patients who have not changed
obtain more or less the same scores (the capacity to
minimize this noise can be called reproducibility). It
follows that, to be of use, the ability of an
instrument to show change when such change
occurs has to be combined with its stability under
unchanged conditions.
An example of an index of responsiveness is the
ratio of the magnitude of change that corresponds
to the minimally important difference, to the
variability in score in stable subjects. Alternatively,
the minimally important difference can be related
to the variability associated with measuring
differences in subjects who are changing. Investi-
gators have suggested other measurements of
responsiveness, but they all rely on some way of
relating signal to noise.11± 14
Another essential measurement property of an
instrument is the extent to which one can under-
stand the magnitude of any differences between
treatments that a study demonstrates Ð the instru-
ment's interpretability. If a treatment improves
HRQL score by three points relative to control,
what are we to conclude? Is the treatment effect
very large, warranting widespread dissemination,
or is it trivial, suggesting the new treatment should
be abandoned? This question highlights the
importance of being able to interpret the results
of our HRQL questionnaire scores.
While our capacity to interpret results remains
limited, investigators are adducing more and more
information to enhance instrument interpretabil-
ity. Researchers have developed a number of
strategies to address this difficult issue. Successful
strategies have three things in common. First, they
require an independent standard of comparison.
Second, this independent standard must itself be
interpretable. Third, there must be at least a
moderate relationship between changes in ques-
tionnaire score and changes in the independent
standard. We have found that a correlation of 0.5
approximates the boundary between an acceptable
and unacceptable relationship for establishing
interpretability.
In our own work, we have often used global
ratings of change (patients classifying themselves
as unchanged, or experiencing small, medium, and
large improvements or deteriorations) as the
independent standard. We construct our disease-
specific instruments using seven-point scales with
an associated verbal descriptor for each level on
the scale. For each questionnaire domain, we
divide the total score by the number of items so
that domain scores can range from 1 to 7. Using
this approach to framing response options, we
have found that the smallest difference that
patients consider important is often approximately
0.5 per question. A moderate difference corre-
sponds to a change of approximately 1.0 per
question, and changes of greater than 1.5 can be
considered large. So, for example, in a domain
with four items, patients will consider a one point
change in two or more items as important. This
finding seems to apply across different areas of
function, including dyspnea, fatigue, and emo-
tional function in patients with chronic airflow
limitation;15 symptoms, emotional function, and
activity limitations in both adult16 and child17
asthma patients, and parents of child asthma
patients;18 and symptoms, emotional function,
and activity limitations in adults with rhinocon-
junctivitis.19 Similar observations may be derived
from reports of others.20
The approach that we have just described relies
on within-patient comparisons as the indepen-
dent standard. One alternative is between-patient
comparisons. In one example of this approach,
we formed groups of seven patients with chronic
airflow limitation participating in a respiratory
rehabilitation program. Each patient completed
the Chronic Respiratory Questionnaire. The
patients conversed with one another long enough
to make judgements about their relative experi-
ence of fatigue in daily life. While there was a
bias in their assessment (patients generally
considered themselves better off than one an-
other), their relative ratings allows estimates of
what differences in Chronic Respiratory Ques-
tionnaire score constitute small, medium, and
large differences. The results were largely con-
gruent with the findings from the within-patient
rating studies.21
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USING QUALITY OF LIFE MEASUREMENTS IN PHARMACOEPIDEMIOLOGY RESEARCH 607

Investigators can also use measures that physi-
cians, through long experience, already know well,
as independent standards. For example, scores on
a generic measure of HRQL, the Sickness Impact
Profile (SIP), range from an average of 8.2 in
patients with American Rheumatism Association
arthritis class I, to 25.8 in class IV.22 Another
often as many as 100, to prevent a single adverse
event.26, 27 Thus, the hypothetical treatment with a
mean difference of 0.25 and an NNT of four
proves to have a powerful effect.
We have shown that this issue is much more
than hypothetical.28 In a crossover randomized
trial in asthmatic patients comparing the short
standard would be obtained by administering acting inhaled -agonist salbutamol to the long
questionnaires to patients before and after an
intervention of known effectiveness with which
clinicians are familiar, so that they can see the
change in score associated with response to
treatment. For example, patients shortly after hip
replacement have scores of 30 on the SIP, scores
which decrease to less than 5 after full convales-
cence.23 Relationships between HRQL and a
variety of marker states can also be useful: SIP
scores in patients with chronic airflow limitation
severe enough to require home oxygen are
approximately 24;24 scores in patients with
chronic, stable angina are approximately 11.5.25
Clinicians and investigators tend to assume that
if the mean difference between a treatment and a
control is appreciably less than the smallest change
that is important, then the treatment has a trivial
effect. This may not be so. Let us assume that a
randomized clinical trial (RCT) shows a mean
difference of 0.25 in a questionnaire with a
minimally important difference (MID) of 0.5.
One may conclude that the difference is unim-
portant, and the result does not support adminis-
tration of the treatment. This interpretation
assumes that every patient given treatment scored
0.25 better than they would had they received the
control and ignores possible heterogeneity of
treatment effect. Depending on the true distribu-
tion of results, the appropriate interpretation may
be different.
Consider a situation where 25% of the treated
patients improved by a magnitude of 1.0, while the
other 75% did not improve at all (mean change of
0). This would mean that the 25% of treated
patients obtained moderate benefit from the
intervention. Using the methodology that has
recently been developed for interpreting the
magnitude of treatment effects, the number needed
to treat (NNT), investigators have found that
clinicians commonly treat 25 to 50 patients, and
acting beta inhaled -agonist salmeterol, we found
a mean difference of 0.3 between groups in the
activity dimension of the asthma quality of life
questionnaire (AQLQ). This mean difference
represents slightly more than half the minimal
important difference in an individual patient.
Knowing that the minimal important difference
is 0.5 allows us to calculate the proportion of
patients who achieved benefit from salmeterol Ð
that is, the proportion who had an important
improvement (greater than 0.5 in one of the
HRQL domains) while receiving salmeterol rela-
tive to salbutamol. For the activity domain of the
AQLQ, this proportion proved to be 2.2. The
NNT is simply the inverse of the proportion who
benefit, in this case 4.5. Thus, clinicians thus need
to treat fewer than five patients with salmeterol to
ensure than one patient obtains an important
improvement in their ability to undertake activities
of daily living.
In another randomized trial examining the effect
of a respiratory rehabilitation program in patients
with chronic lung disease, we found a mean
difference between rehabilitation patients and the
community controls of 0.40 in the emotions
domain of the Chronic Respiratory Questionnaire.
This difference is appreciably less than the value of
0.5 that represents the minimal important differ-
ence in an individual patient. However, the data
from the trial allow us to calculate the proportion
of patients who were 0.5 points or more better in
their emotional function while receiving rehabilita-
tion than would have been the case had they been
in the community control group. This turns out to
be 0.30, which translates into an NNT of 3.3
patients.
This discussion emphasizes that to interpret the
results of HRQL measurement in pharmacoepide-
miology studies requires clinicians to be aware of
the changes in score that constitute trivial, small,
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608 PHARMACOEPIDEMIOLOGY
medium, and large differences in HRQL. Further,
looking at mean differences between groups can be
misleading. The distribution of differences is
critical, and can be summarized in an informative
manner using the NNT.
QUALITY OF LIFE MEASUREMENT
INSTRUMENTS: TAXONOMY AND
POTENTIAL USE
During the last decade, clinical journals have
started to publish trials in which HRQL instru-
ments are the primary outcome measures. With the
expanding importance of HRQL in evaluating new
therapeutic interventions, investigators (and read-
ers) are faced with a large array of instruments.
Researchers have proposed different ways of
categorizing these instruments, according to the
purpose of their use, into instruments designed for
screening, providing health profiles, measuring
preference, and making clinical decisions,29 or into
discriminative and evaluative instruments (as
above).
We have also suggested a taxonomy based on
the domains of HRQL which an instrument
attempts to cover.30 According to this taxonomy,
an HRQL instrument may be categorized, in a
broad sense, as generic or specific. Generic instru-
ments cover (or at least aim to cover) the complete
spectrum of function, disability, and distress of the
patient, and are applicable to a variety of
populations. Within the framework of generic
instruments, health profiles and utility measures
provide two distinct approaches to measurement
of global quality of life. Specific instruments are
focused on disease or treatment issues specifically
relevant to the question at hand.
GENERIC INSTRUMENTS
Health Profiles
Health profiles are single instruments that measure
multiple different aspects of quality of life. They
usually provide a scoring system that allows
aggregation of the results into a small number of
scores and sometimes into a single score (in which
case, it may be referred to as an index). As generic
measures, they are designed for use in a wide
variety of conditions. For example, one health
profile, the Sickness Impact Profile (SIP) contains
12 ``categories,'' which can be aggregated into two
dimensions and five independent categories, and
also into a single overall score.31 The SIP has been
used in studies of cardiac rehabilitation,32 total hip
joint arthroplasty,33 and treatment of back pain.34
In addition to the SIP, there are a number of other
health profiles available: the Nottingham Health
Profile,35 the Duke ± UNC Health Profile,36 and
the McMaster Health Index Questionnaire.37
Increasingly, a collection of related instruments
from the Medical Outcomes Study38 have become
the most popular and widely used generic instru-
ments. Particularly popular is one version that
includes 36 items, the SF-36.39± 41
While each health profile attempts to measure
all important aspects of HRQL, they may slice the
HRQL pie quite differently. For example, the
McMaster Health Index Questionnaire follows the
World Health Organization approach and identi-
fies three dimensions: physical, emotional, and
social. The Sickness Impact Profile includes a
physical dimension (with categories of ambulation,
mobility, body care, and movement), a psychoso-
cial dimension (with categories including social
interaction and emotional behavior), and five
independent categories including eating, work,
home management, sleep and rest, and recreations
and pastimes.
General health profiles offer a number of
advantages to the clinical investigator. Their
reproducibility and validity have been established,
often in a variety of populations. When using them
for discriminative purposes, one can examine and
establish areas of dysfunction affecting a particular
population. Identification of these areas of dys-
function may guide investigators who are con-
structing disease-specific instruments to target
areas of potentially greatest impact on the quality
of life. Health profiles, used as evaluative instru-
ments, allow determination of the effects of an
intervention on different aspects of quality of life,
without necessitating the use of multiple instru-
ments (and thus saving both the investigator's and
the patient's time). Because health profiles are
designed for a wide variety of conditions, one can
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USING QUALITY OF LIFE MEASUREMENTS IN PHARMACOEPIDEMIOLOGY RESEARCH
potentially compare the effects on HRQL of
different interventions in different diseases. Pro-
files that provide a single score can be used in a
cost ± effectiveness analysis, in which the cost of an
intervention in dollars is related to its outcome in
natural units (see Chapter 35).
The main limitation of health profiles is that
they may not focus adequately on the aspects of
quality of life specifically influenced by a parti-
cular intervention. This may result in an inability
of the instrument to detect a real effect in the area
of importance (i.e., lack of responsiveness). We
will return to this issue when we discuss the
alternative approach, specific instruments.
Utility Measurement
Economic and decision theory provides the under-
lying basis for utility measures (see Chapter 35).
The key elements of an utility instrument are, first
that it is preference based, and second, that scores
are tied to death as an outcome. Typically, HRQL
can be measured as a utility measure using a single
number along a continuum from death (0.0) to full
health (1.0). The use of utility measures in clinical
studies requires serial measurement of the utility of
the patient's quality of life throughout the study.
There are two fundamental approaches to utility
measurement in clinical studies. One is to ask
patients a number of questions about their
function. Based on their responses, patients are
classified into one of a number of categories. Each
category has a utility value associated with it, the
utility having been established in previous ratings
by another group (such as a random sample of the
general population). This approach is typified by
two widely used instruments, the Quality of Well-
Being Scale42± 44 and the Health Utilities Index.45
The second approach is to ask patients to make
a single rating which takes into account all aspects
of their quality of life.46 This rating can be made
many ways. The ``standard gamble'' asks patients
to choose between their own health state and a
gamble in which they may die immediately or
achieve full health for the remainder of their lives.
Using the standard gamble, patients' utility or
HRQL is determined by the choices they make, as
the probabilities of immediate death or full health
609
are varied. Another technique is the ``time trade-
off,'' in which subjects are asked about the number
of years in their present health state they would be
willing to trade off for a shorter life span in full
health.
A major advantage of utility measurement is its
amenability to cost ±utility analysis (see Chapter
35). In cost ±utility analysis, the cost of an
intervention is related to the number of quality
adjusted life years (QALYs) gained through
application of the intervention. Cost per QALY
may be compared and provide a basis for
allocation of scarce resources among different
healthcare programs. Results from the utility
approach may thus be of particular interest to
program evaluators and health policy decision
makers.
However, utility measurement also has limita-
tions. Utilities can vary depending on how they are
obtained, raising questions of the validity of any
single measurement.47, 48 Utility measurement does
not allow the investigator to determine which
aspects of HRQL are responsible for changes in
utility. Finally, utilities potentially share the
disadvantage of health profiles, in that they may
not be responsive to small but still clinically
important changes.
SPECIFIC INSTRUMENTS
An alternative approach to HRQL measurement is
to focus on aspects of health status that are specific
to the area of primary interest. The rationale for
this approach lies in the increased responsiveness
that may result from including only those aspects
of HRQL that are relevant and important in a
particular disease process or even in a particular
patient situation. One could also focus an instru-
ment only on the areas that are likely to be affected
by a particular drug. This latter approach is
advanced in the design and conduct of randomized
controlled trials in individual patients ÐN-of-1
randomized clinical trials49 (see Chapter 37).
In other situations, the instrument may be
specific to the disease (instruments for chronic
lung disease, for rheumatoid arthritis, for cardio-
vascular diseases, for endocrine problems, etc.);
specific to a population of patients (instruments
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610 PHARMACOEPIDEMIOLOGY
designed to measure the HRQL of the frail elderly,
who are afflicted with a wide variety of different
diseases); specific to a certain function (question-
naires that examine emotional or sexual function);
or specific to a given condition or problem (such as
pain) that can be caused by a variety of underlying
pathologies. Within a single condition, the instru-
ment may differ depending on the intervention.
For example, while success of a disease modifying
agent in rheumatoid arthritis should result in
improved HRQL by enabling a patient to increase
performance of physically stressful activities of
daily living, occupational therapy may achieve
improved HRQL by encouraging family members
to take over activities formerly accomplished with
difficulty by the patient. Appropriate disease-
specific HRQL outcome measures should reflect
this difference.
Specific instruments can be constructed to
reflect the ``single state'' (how tired have you been:
very tired, somewhat tired, full of energy) or a
``transition'' (how has your tiredness been: better,
the same, worse).50 Theoretically, the same could
be said of generic instruments, although none of
the available generic instruments has used the
transition approach. Specific measures can inte-
grate aspects of morbidity, including events such
as recurrent myocardial infarction.51
The disease-specific instruments may be used for
discriminative purposes. They may aid, for exam-
ple, in evaluating the extent to which a primary
symptom (for example dyspnea) is related to the
magnitude of physiological abnormality (for ex-
ample exercise capacity).52 Disease-specific instru-
ments can be applied for evaluative purposes to
establish the impact of an intervention on a
specific area of dysfunction, and hence aid in
elucidating the mechanisms of drug action.53
Guidelines provide structured approaches for
constructing specific measures.54 Whatever ap-
proaches one takes to the construction of dis-
ease-specific measures, a number of head-to-head
comparisons between generic and specific instru-
ments suggest that the latter approach will fulfill
its promise of enhancing responsiveness.55 ± 60
In addition to the likelihood of improved
responsiveness, specific measures have the advan-
tage of relating closely to areas routinely explored
by the physician. For example, a disease-specific
measure of quality of life in chronic lung disease
focuses on dyspnea during day-to-day activities,
fatigue, and areas of emotional dysfunction,
including frustration and impatience.61 Specific
measures may therefore appear clinically sensible
to the physician.
The disadvantages of specific measures are that
they are (deliberately) not comprehensive, and
cannot be used to compare across conditions or, at
times, even across programs. This suggests that
there is no one group of instruments that will
achieve all the potential goals of HRQL measure-
ment. Thus, investigators may choose to use
multiple instruments, an issue we will deal with
in the next section.
USE OF MULTIPLE QUALITY OF LIFE
MEASURES IN CLINICAL STUDIES
Clinical investigators are not restricted to using a
single instrument in their studies, and investigators
will often conclude that a single instrument cannot
yield all the relevant information. For example,
utility and disease-specific measures contribute
quite different sorts of data, and an investigator
may want to use one of each.
Another, somewhat different way of using
multiple instruments is to administer a battery of
specific instruments. An example of such an
approach was a double blind, randomized trial of
three antihypertensive agents in primary hyperten-
sion.7 The investigators identified five dimensions
of health they were measuring: the sense of well-
being and satisfaction with life, the physical state,
the emotional state, intellectual functioning, ability
to perform in social roles, and the degree of
satisfaction from those roles. Even within these
five dimensions, additional components were
identified. For example, separate measurements
of sleep and sexual function were made. Patients
taking one of the three drugs under investigation,
captopril, scored better on measures of general
well-being, work performance, and life satisfac-
tion. The lesson for the clinician is clearly
important: one can have an impact on not only
the length, but also the quality of the patient's life
according to choice of antihypertensive agent.
{Jobs}0688jw/makeup/688ch36.3d
USING QUALITY OF LIFE MEASUREMENTS IN PHARMACOEPIDEMIOLOGY RESEARCH
This approach, although comprehensive, has
limitations. First, investigators must find a valid,
responsive instrument for every attribute they wish
to measure. Second, it is possible (indeed likely)
that only some of the instruments chosen will show
differences between the treatments under investi-
gation. Unless one of the instruments has been
designated as the primary measure of outcome
before the study started, different results in
different measures may make interpretation diffi-
cult. The greater the number of instruments used,
the greater the probability that one or more will
favor one treatment or the other, even if the
treatments' true effectiveness is identical. Thus, the
 error (the probability of finding an apparent
difference between treatments when in fact their
outcomes do not differ) increases with each new
instrument used. Although this problem may be
dealt with through statistical adjustment for the
number of instruments used, such adjustment is
often not made.62
Another problem occurs if only a small propor-
tion of the instruments used favor an intervention
(or if some measures favor one treatment and
other instruments favor the other). In these
situations, the clinician may be unsure how to
interpret the results. The use of multiple instru-
ments opens the door to such potential contro-
versy.
A final limitation of using a battery of instru-
ments is that it gives no indication of the relative
importance of various areas of dysfunction to the
patient. For example, had Croog et al.7 found that
one antihypertensive agent disturbed sleep, while
another had an adverse impact on sexual function,
their approach would not have allowed determina-
tion of which drug had a greater net adverse
impact on patients' lives.
THE FUTURE
The considerations we have raised suggest a step-
by-step approach to addressing issues of HRQL in
pharmacoepidemiology studies.63 Clinicians must
begin by asking themselves whether investigators
have addressed all the important effects of treat-
ment on patients' quantity and quality of life.64, 65
611
If they have not, clinicians may have more
difficulty applying the results to their patients.
If the study has addressed HRQL issues, have
investigators chosen the right instruments? In
particular, does evidence suggest the measure(s)
used are valid measures of HRQL? If so, and the
study failed to demonstrate differences between
groups, is there good reason to believe the
instrument is responsive in this context? If not,
the results may be a false negative, failing to show
the true underlying difference in HRQL.
Whatever the differences between groups, the
clinician must be able to interpret their magnitude.
Knowledge of the difference in score that repre-
sents small, medium, and large differences in
HRQL will be very helpful in making this
interpretation. Clinicians must still look beyond
mean differences between groups, and consider the
distribution of differences. The number of patients
needed to treat to ensure that a single patient
achieves an important benefit in HRQL offers one
way of expressing results that clinicians are likely
to find meaningful.
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