Transcript (P2-080) DEMENTIA SCREEENING: IMPLICATIONS OF AGE, APOE GENOTYPE, PHARMACOECONOMIC FACTORS J. Wesson Ashford, M.D., Ph.D., Helena C.

(P2-080)
DEMENTIA SCREEENING: IMPLICATIONS OF AGE, APOE GENOTYPE, PHARMACOECONOMIC FACTORS
J. Wesson Ashford, M.D., Ph.D., Helena C. Kraemer, Ph.D., Jared R. Tinklenberg, M.D.,
Ruth O’Hara, Ph.D., Joy L. Taylor, Ph.D., Jerome A. Yesavage, MD.
Stanford / VA Alzheimer Center, VA Palo Alto Health Care System, &
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA, USA.
ABSTRACT
Contact e-mail: [email protected]
BACKGROUND
In an era of increasing pressure to detect and manage
prevalent disorders as early in their course as possible,
screening has become an accepted norm for many
conditions. If medical professionals and the public accept
screening for hypertension, diabetes, breast cancer, and
colon cancer, why is there no widespread demand to screen
for dementia? Detection of dementia - the most disabling
common condition of later life (Aguerro-Torres H et al., 2001)
- is currently left to chance.
Screening was defined in 1951 by the US Commission on
Chronic Illness as, "the presumptive identification of
unrecognized disease or defect by the application of tests,
examinations or other procedures which can be applied
rapidly. Screening tests sort out apparently well persons who
probably have a disease from those who probably do not. A
screening test is not intended to be diagnostic. Persons with
positive or suspicious findings must be referred to their
physicians for diagnosis and necessary treatment“ (Last,
2000).
However, screening tests for dementia are generally not
recommended by health care organizations. The purpose of
this presentation is to determine what the costs and benefits
are with respect to the justification for screening.
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Specificity = TN/P’
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10
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Predictive value of a:
Positive test = PVP = TP/Q
Negative test = PVN = TN/Q’
Statistical Significance (2X2 Chi Square Test)
means only that there is some non-random
association between disorder (D) and test (T), not
that the test Is a worthwhile one
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-2
0
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90
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animals 1 m
AUC = 0.868
animals 30 s
AUC = 0.828
MMSE
AUC = 0.965
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Date+3 Rec
AUC = 0.875
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BAS
AUC = 0.983
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0.1000
0.0100
0.0010
- plot of sensitivity versus specificity
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0.01
$W = Cost–Worthiness Calculation
0.0001
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$250,000
$225,000
$200,000
$175,000
$150,000
$125,000
$100,000
$75,000
$50,000
$25,000
$0
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100
$C (estimate of cost)
Estimated Age-related Cost
of Alzheimer Screening
Benefit: $10,000 - 0
Benefit: $25,000 - 0
Benefit: $100,000 - 0
Benefit: cure = $240,000
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Cost Worthiness Calculations (above “0” is cost-worthy or feasible test price)
Cost-Worthy Test Evaluation
Sensitivity = 0.9, Specificity = 0.9
Cost-Worthy Test Evaluation
Sensitivity = 0.9, Specificity = 0.9
$1,000
$900
$800
$700
$600
$500
$400
$300
$200
$100
$0
-$100
Benefit: $5,000 - 0
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$100
$90
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$70
$60
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$40
$30
$20
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$0
-$10
-$20
Benefit: $5,000 - 0
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Benefit: $10,000 - 0
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Benefit: $100,000 - 0
Benefit: cure = $240,000
Alzheimer’s disease is not a dichotomous diagnosis
but a continuum (Ashford & Schmitt, 2001)
- Diagnosis would be better described with a
probabilistic statement (AUC vs disease point)
- Item Response Theory would better calculate
probability (Modern Test Theory)
- Item Response Theory and Factor Analysis allow
combination of test components
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Aguero-Torres H, von Strauss E, Viitanen M, Winblad B, Fratiglioni L. Institutionalization in the elderly: the role
of chronic diseases and dementia. Cross-sectional and longitudinal data from a population-based study. Clin
Epidemiol. 2001 Aug;54(8):795-801.
Ashford JW. APOE genotype effects on Alzheimer's disease onset and epidemiology. Journal of Molecular
Neuroscience 23:155-163, 2004.
Ashford, JW, Borson S, O’Hara R, Dash P, Frank, Robert P, Shankle WR, Tierney MC, Brodaty H, Schmitt FA,
Kraemer HC, Buschke H. Should older adults be screened for dementia? Alzheimer’s & Dementia. 2:76–
85,2006
Cost-Worthy Test Evaluation
Se=0.9; Sp=0.9
Benefit = $50,000 - 0; False Pos = $500
Ashford JW, Schmitt FA. Modeling the time-course of Alzheimer dementia. Cur Psychiatry Rep. 2001
Feb;3(1):20-8.
Ashford JW, Shan M, Butler S, Rajasekar A, Schmitt FA. Temporal quantification of Alzheimer's disease
severity: 'time index' model. Dementia. 1995 Sep-Oct;6(5):269-80
Kraemer HC. Evaluating Medical Tests. Sage Publications, Inc., Newbury Park, California, 1992.
mean
ApoE 4/4
ApoE 3/4
ApoE 3/3
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AGE
Benefit: $100,000 - 0
AGE
Benefit: cure = $240,000
mean
ApoE 4/4
ApoE 3/4
ApoE 3/3
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Benefit: $10,000 - 0
Benefit: $25,000 - 0
Cost-Worthy Test Evaluation
Se=0.9; Sp=0.9
Benefit = $50,000 - 0; False Pos = $500
The cost-worthiness must be assessed:
- Apply the test cost and the costs of false positive
and false negative results
- Apply the benefits of correct positive (deduct
treatment costs) and negative results
- Consider with respect to the annual incidence of
the disease
REFERENCES
Benefit: $25,000 - 0
$500 for further evaluation
(time, stress of suspecting dementia)
(Kraemer, 1992)
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COST
$C = cost of a false positive diagnosis
$W > ($B x I x Se) – ($C x (1-I) x (1-Sp)) - $T
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Benefit: $5,000 - 0
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True negative = real peace of mind (priceless)
False negative = false peace of mind (no price)
I = incidence (new occurrences each year, by age)
Se = sensitivity of test = True positive / I
Sp = specificity of test
= True negative / (1-I) = (1-False positive/(1- I)
$T = cost of test, time to take (Subject, Tester)
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Estimated Age-related Benefit of
Early Alzheimer Treatment (linear drop 50-100y/o)
Benefit for a cure = $240,000, independent of age
Earlier diagnosis may mean proportionally greater
savings
Save up to $50,000 (e.g., nursing home cost for 1 year)
(after treatment cost deduction at age 50, none at age
100) (cost-savings may vary according to locale)
May calculate savings with respect to usual diagnostic
practice
Many additional tangible and intangible benefits
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$B (estimate of benefit)
BENEFIT
$B = benefit of a true positive diagnosis
Estimate: (100 years – age ) x $1000
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The value of the test must be calculated with
respect to the risk of the disease
- In the specific population to which it is being
applied
- Risk is affected by age, genotype, many other
factors
- Accounting for a priori probability is Bayesian
analysis
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(For estimates, see Ashford, 2004; Raber et al., 2004)
Factors for Deciding whether
a Screening Test is Cost-Effective
Benefit of a true positive screen (major issue)
Benefit of a true negative screen (minimal)
Cost of a false positive screen (may need for many)
Cost of a false negative screen (minimal)
Incidence of the disease (in population)
Test sensitivity (in population)
Test specificity (in population)
Test cost (range from free to $2000 for PET scan)
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mean rate
APOE 4/4
APOE 3/4
APOE 3/3
presenilin
0.0001
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Alzheimer Incidence by APOE genotype
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Dementia rate, for Td = 5 yrs
Males, 2t = 8.2yrs
Females, 2t = 7.5 yrs
Alzheimer incidence
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False Positive Rate (%) (1-Specificity)
U.S. mortality rate by age
1999 CDC / 2000 census
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ROC analysis provides independent values of test
performance (shape, AUC = area under curve)
- How the screening test values affect the normal
and patient populations
- Plots of their relationship with respect to each
other (specificity vs sensitivity)
- Data must be derived from the represented
population!!!
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U.S. Mortality, Alzheimer Incidence (I)
1.0000
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Estimated years into illness
(Random: Sensitivity + Specificity = 1)
ROC (Receiver Operator Curve) Analysis
True Positive Rate (%) (Sensitivity)
Sensitivity = TP/P
Q’=1-Q
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P’ = 1 - P
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Number of people/yr
Q=level
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P = prevalence
MMSE score
TN
(Normal vs Mild AD, MMS>19)
Price of a false positive
diagnosis - further
evaluation
Commercial Relationship: J.W. Ashford, None; H.C. Kraemer, None; J.R. Tinklenberg,
None; R. O'Hara, None; J.L. Taylor, None; J.A. Yesavage, None.
FP
BRIEF ALZHEIMER SCREEN
Cost Justified for
Dementia Screen
Conclusions: Conservative estimations and statistical calculations suggest that
currently available dementia screening tests are cost-worthy for annual use,
depending on the age and genotype of the individual to be screened. Note that the
biggest factors determining cost-worthiness are incidence and benefit of identifying
the disease. The exact sensitivity and specificity of the test used is not critical.
FN
ROC Curve (Mendiondo et al., 2003)
Cost Justified for
Dementia Screen
Results: The benefit of a test with a Se and Sp of 0.8 would become positive for
annual administration beginning at 70 y/o if the test were free and at 75 y/o if the test
cost $40 per administration, for a benefit decreasing from $50,000 to 0 from age 50 to
age 100. A test with Se and Sp of 0.9 would be worth giving annually beginning at 65
y/o if it cost only $10 to administer. Values were calculated for APOE genotype (using
an estimate of age-specific incidence by genotype), with a test having Se and Sp =
0.9. For an e4/4 individual a test would be worth $30 for annual screening beginning
at 50 y/o, for an e3/4, beginning at 63 y/o and for an e3/3, beginning at 74 y/o.
TP
SUMMARY / IMPLICATIONS
Estimate MMSE as a function of time
Dollar Benefit from
Early Diagnosis and Treatment
$W = ($B x I x Se) - ($C x (1-I) x (1-Sp)) - $T
Diagnosis-
Test-
Yearly Hazard
Methods: To determine “cost-worthiness” ($W), estimates are needed for the test to
be evaluated, including: sensitivity (Se), specificity (Sp), cost of administration ($T),
and level of disease being used for identification. Additional information required
includes: incidence ( I ), benefit of a true-positive screen ($B – for example: estimated
to decrease from $50,000 at age 50 to $0 at age 100), and cost of a false-positive
screen ($C - estimated at $500 for a secondary test to rule out dementia). Incidence
of dementia and Alzheimer’s disease are known to be a function of age and APOE
genotype. The following equation was examined:
Diagnosis+
Test+
Alzheimer Continuum (Ashford et al., 1995)
Cost Justified for
Dementia Screen
Objective(s): The purpose of this presentation is to demonstrate mathematically the
factors required to judge the value - “cost-worthiness” - of a screening test.
THE BASIC 2X2 OF EVALUATION
Cost Justified for
Dementia Screen
Background: Though dementia is one of the most common problems affecting the
elderly, no standard has been developed to screen for signs or symptoms of
dementia. Those whose dementia has not been identified are missing the benefit of
current therapies. Consequently, there is a growing awareness of the public-health
need to screen for this common problem (see Ashford et al., 2006).
RESULTS
METHODS
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Last JM. Editor, A Dictionary of Epidemiology, International Epidemiological Association 1st Edn, 1983, 2nd
Edn, 1987, 3rd Edn, 1995, 4th Edn, 2000.
Mendiondo MS, Ashford JW, Kryscio RJ, Schmitt FA. Designing a brief Alzheimer screen (BAS). J Alzheimers
Dis. 2003 Dec 5:391-398.
Raber J, Huang, Y, Ashford JW. ApoE genotype accounts for the vast majority of AD risk and AD
neuropathology. Neurobiology of Aging 25(5):641-50 2004.
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Poster presented at the International Conference on Alzheimer’s disease, Madrid, July 17, 2006.
Corresponding author: J. Wesson Ashford, M.D., Ph.D., Stanford / VA Alzheimer Center, VA Health Care
System (151Y-PAD), 3801 Miranda Ave., Palo Alto, CA 94304, USA; Tel.: (650) 852-3287; Fax: (650) 8523297: email: [email protected]