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Diagnostic considerations in Alzheimer disease. Predictive value of intrusion errors as a differential diagnostic sign of Alzheimer disease

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LETTERS
Diagnostic Considerations
in Alzheimer Disease
as defined for this study, should therefore be helpful in
differentiating Alt from other dementias” should be considered tenuous until confirmed by further data from large
samples.
Predictive Value of Intrusion Errors
As a Differential Diagnostic Sign
of Alzheimer Disease
Institute for Psychopharmacologic Research
1842 Beacon St
Brookline. M A 02146
Roland J. Branconnier, MA
I read with interest the paper by Drs Fuld et a1 entitled
“Intrusions As a Sign of Alzheimer Dementia: Chemical
and Pathological Verification” [2].The authors have drawn
the conclusion that intrusion errors are a useful differential
diagnostic sign for Alzheimer dementia (AD) because
those errors have significant discriminative validity. However, the establishment of discriminative validity of a diagnostic test under experimental conditions is not sufficient
to predict the usefulness of the test when applied to an
unselected population [5j. This is because the predictive
value of a positive test result is a function of the prevalence
(a priori probability) of a disease in the population [31.
Concerning intrusion errors, the critical question to be answered is: What is the a posteriori probability that a demented patient who makes such errors does, in fact, have
AD?
Such a posteriori probabilities or predictive values cannot be determined from experimental data alone but require the application of predictive value analysis, a series of
statistical methods based on Bayes’ theorem [ l , 31. From
the data presented in the paper it is possible to evaluate the
sensitivity, specificity, and predictive value of intrusion errors as a differential diagnostic sign of AD. Sensitivity can
be defined as the percentage of positive results obtained
when the test is administered to persons who are known to
have a disease. In this case, 19 of 21 patients with a diagnosis of AD made intrusion errors. Thus, the sensitivity of
that sign is 19/21, or 90%. Specificity can be defined as the
percentage of negative test results obtained from persons
known to be free of a disease. Eleven of 17 patients with
other dementias did not make intrusion errors. Thus, the
specificity is 11/17, or 65%. Epidemiological data reveal
that 60% of all cases of dementia are due to A D [ 4 ] .Since
the a priori probability that any demented patient has A D is
60%, and because intrusion errors have a sensitivity of
90% and specificity of 65%, by application of Bayes’
theorem the a posteriori probability that a demented patient who makes an intrusion error has A D is 79%.
While this predictive value may appear to be satisfactory,
it can be shown that if the intrusion error test is replaced by
flipping a coin (a coin has a sensitivity equal to 50% and
specificity of 50%), and a “head” indicates AD, then the a
posteriori probability that “heads” is a sign of A D is 60%.
Since the gain in differential diagnostic accuracy of the intrusion error test is only 19% over random selection, it can
be concluded that a substantial portion of the observed
differential diagnostic accuracy of that test for A D results
from the 60% prevalence rate of A D among dementias.
Moreover, since only 38 patients were studied, the 75%
confidence limits of the sensitivity and specificity of the test
can be shown to be 77 to 100% and 53 to 7796, respectively. Therefore, the authors’ conclusion that “intrusions,
RejerenceJ
1. Bayes T An essay toward solving a problem in the doctrine of
chance. Phil Trans Royal Soc 53:370-418, 1763
2. Fuld PA, Katzman R, Davies P, Terry RD: Intrusions as a sign
of Alzheimer dementia: chemical and pathological verification.
Ann Neurol 11:155-159, 1982
3. Galen RS, Gambino SR: Beyond Normality: The Predictive
Value and Efficiency of Medical Diagnoses. New York, Wiley,
1975
4. Mortirner JA, Schuman LM, French LR: Epidemiology of dementing illness. In Mortimer JA, Schuman LM (eds): The
Epidemiology of Dementia. New York, Oxford University
Press, 1981
5. Vecchio TJ: Predictive value of a single diagnostic test in unselected populations. N Engl J Med 274:1171-1173, 1966
Neuropathological Basis
for Diagnosis of Alzheimer’s Disease
Meta A. Neumann, MS,’ and Robert Cohn, M D t
With regard to the article on intrusions as a sign of Alzheimer’s disease by Fuld et al, we were surprised that these
eminent authors considered the presence of plaques in only
three cortical areas sufficient to establish the diagnosis of
AD. The presence of plaques was alluded to three times in
the article, while neurofibrillary changes were never mentioned. The thioflavin S method that was used clearly depicts diseased neurons as well as plaques. In more than 25
years’ experience with the study of brains of all autopsied
cases at a large mental hospital (Saint Elizabeths Hospital,
Washington, DC) together with a review we conducted of
the clinical histories of these patients, we observed that patients with argyrophilic plaques alone did not show the
specific clinical correlates of AD [2, 31, although memory
loss, usually for recent events only, was apparent.
Since “intrusions” as defined by the authors must occur
in conditions other than AD, and even in normal subjects,
the test obviously is not specific. Having the patient perform arithmetical operations, draw various maps, or carry
out simple geometrical problems generates a clearer and
less equivocal index of intellectual deterioration when repeated at intervals of several months. It must be emphasized that no clinical test can distinguish between AD
and other cerebral degenerative processes such as Pick’s disease or progressive subcortical gliosis [4].
In these insidious degenerative diseases, the age of onset
can hardly be established; moreover, A D as a specific
clinical-neuropathological entity is the same process, irrespective of the age at onset or age at death.
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errors, differential, signs, disease, considerations, values, prediction, alzheimers, diagnostika, intrusion
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