J Clin Epidemiol Vol. 41, No. 6, pp. 613-614, 1988
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Printed in Great Britain. All rights reserved
Letter to the Editors
THE INTERNATIONAL AGRANULOCYTOSIS
AND APLASTIC ANEMIA STUDY (IAAAS)
The IAAAS authors’ reply [l] to our critique [2]
raises three issues that merit further discussion:
(1) confusion about the timing of drug exposure
vs its duration; (2) the distinction between
hospital and community cases and controls; and
(3) repeated complaints that we engage in
“speculation.”
We believe that the most fundamental flaw in
the IAAAS is its failure to consider the timing
of drug exposure with respect not only to the
occurrence of the blood dyscrasia but also to the
onset of treatment. As we noted in our critique,
the risk posed by a drug for a particular event
is not generally the same in the sixth month of
chronic therapy as in the first or second week of
treatment. This is a well-accepted principle in
clinical pharmacology. For many immunologic
and idiosyncratic reactions, sensitive persons
react quickly, and nonsensitive persons may not
react at all. For dose-related toxicities, adverse
events may not appear until the cumulative dose
is high. And for adverse effects with prolonged
latent periods (e.g. carcinogenic effects), many
years may pass before the outcome develops. In
other words, the incidence density for adverse
drug reactions varies with respect to time after
initiating treatment. Ideally, therefore, absolute
and relative risks should be analyzed as a func-
tion of time since beginning treatment (e.g. for
each week). The IAAAS authors’ response, in
which they discuss their analyses of duration of
exposure, completely ignores this issue. In the
IAAAS, any period of exposure counts the same
as any other, whether it takes place during the
first week or after 2 years of treatment, as long
as that period falls within the time window
calculated back from the occurrence of the
blood dyscrasia.
Contrary to the IAAAS authors’ reply, it is
not the distinction between hospital- and
community-acquired cases of agranulocytosis or
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aplastic anemia that is unclear. Rather, it is the
reason for the distinction, since control groups
were not selected for each of the two case
groups. We agree that the use of carefully
selected hospitalized patients as a separate con-
trol group for those cases occurring during a
hospital stay would be desirable to control for
severity of underlying illness and opportunity
for drug exposure. The authors claim that such
a control group was unobtainable, “principally
because patients with serious illnesses frequently
were inaccessible for interview” [3]. But why
should such control patients be any less acces-
sible than seriously ill “hospital cases”?
The IAAAS authors repeatedly accuse us of
“speculation,” but they appear unwilling to
distinguish plausible hypothesis from wild con-
jecture. Moreover, they seem to disavow any
responsibility for considering alternative expla-
nations, regardless of their a priori plausibility.
Is it implausible to suggest that rheumatic
disease may be associated with bone marrow
depression? Not only did we cite four references
([8-l l] in our critique [2]) to support this sug-
gestion; it was also confirmed by discussions
with qualified hematologists. Similarly, it hardly
seems conjectural on our part to question
whether certain classes of patients with particu-
lar clinical or sociodemographic characteristics
or specific treatment indications may be at
substantially different risks of drug-induced
blood dyscrasia than other classes of patients.
Such a possibility is supported by Ref. [6] in
our critique [2]; moreover, were it not true,
analgesic-induced blood dyscrasias would con-
stitute a notable exception to the rather robust
finding that the risks of adverse drug effects are
indeed modified by patient characteristics. We
also disagree with the response to our comments
about multiplicative vs additive effects; those
comments are neither speculative nor irrelevant.
614 Letter to the Editors

Although the IAAAS authors claim that they DAVID A. LANE

Department of Theoretical Statistics
did not examine the possible combined effects of
School of Statistics
exposure to more than one drug because of University of Minnesota
insufficient data, use of the logistic model as- Minneapolis, Minnesota
U.S.A.
SUITS multiplicative effects in estimating the
coefficients of risk for each individual drug. TOM A. HUTCHIN~ON
Such complaints about speculation appear to us Departments of Epidemiology and
Biostatistics and of Medicine
to be nothing more than artful scientific dodg- McGill University Faculty of Medicine
ing. It is up to a study’s investigators to design Montreal
and analyze that study in such a way as to Quebec
Canada
examine plausible alternative hypotheses.
We look forward to further discussions of REFERENCES
these scientific issues and hope that such dis- 1
The International Agranulocytosis and Aplastic
cussions can lead to an improvement in the ’ Anemia Study. Reply. J Chron Dis 1987; 40:
design and analysis of case-control studies of 1083-1085.
adverse drug effects. 2. Kramer MS, Lane DA, Hutchinson TA. Analgesic use,
blood dyscrasias, and case-control pharmacoepi-
demiology: a critique of the International Agranulo-
MICHAEL S. KRAMER cytosis and Aplastic Anemia Study. J Chron Dis 1987;
Departments of Epidemiology and 40: 1073-1081.
Biostatistics and of Pediatrics 3. The International Agranulocytosis and Aplastic
McGill University Faculty of Medicine Anemia Study. Risks of agranulocytosis and aplastic
1020 Pine Avenue West anemia: a first report of their relation to drug use with
Montreal, Quebec special reference to analgesics. JAMA 1986; 256:
Canada H3A IA2 1749-1757.