1. (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 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). Objective(s): The purpose of this presentation is to demonstrate mathematically the factors required to judge the value - “cost-worthiness” - of a screening test. 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: $W = ($B x I x Se) - ($C x (1-I) x (1-Sp)) - $T $W = ($B x I x Se) - ($C x (1-I) x (1-Sp)) - $T 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. 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. 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. Contact e-mail: washford@medafile.com SUMMARY / IMPLICATIONS 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!!! 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 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 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 REFERENCES 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 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. 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. 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. THE BASIC 2X2 OF EVALUATION Test+ Test- Diagnosis+ TP FN P = prevalence Diagnosis- FP TN P’ = 1 - P Q=level Q’=1-Q 1 Sensitivity = TP/P Specificity = TN/P’ 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 (Random: Sensitivity + Specificity = 1) ROC (Receiver Operator Curve) Analysis - plot of sensitivity versus specificity 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) 852- 3297: email: ashford@stanford.edu 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) $W = Cost–Worthiness Calculation BENEFIT $B = benefit of a true positive diagnosis Earlier diagnosis may mean proportionally greater savings Estimate: (100 years – age ) x $1000 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 True negative = real peace of mind (priceless) COST $C = cost of a false positive diagnosis $500 for further evaluation (time, stress of suspecting dementia) 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) $W > ($B x I x Se) – ($C x (1-I) x (1-Sp)) - $T (Kraemer, 1992) METHODS RESULTS Alzheimer Continuum (Ashford et al., 1995) ROC Curve (Mendiondo et al., 2003) U.S. Mortality, Alzheimer Incidence (I) Alzheimer Incidence by APOE genotype $C (estimate of cost) $B (estimate of benefit) Cost Worthiness Calculations (above “0” is cost-worthy or feasible test price) (For estimates, see Ashford, 2004; Raber et al., 2004)