1. Statistical Issues for Developing Alzheimer Screening Tests J. Wesson Ashford, M.D., Ph.D. Stanford / VA Alzheimer’s Center VAMC, Palo Alto, California & Helena C. Kraemer, Ph.D. Department of Psychiatry and Behavioral Sciences Stanford University, Palo Alto, California June 19, 2005 Washington, D.C. Slides at: www.medafile.com (Dr. Ashford’s lectures)www.medafile.com

2. Screening for Alzheimer’s Disease What does it mean? Annual assessments (or bi- or semi-) Positive screen recommends more tests Contrast with current lack of system –50% not diagnosed until moderate AD Screening will progressively improve Change over time can be detected

3. AD Can Be Readily Diagnosed A diagnosis of Alzheimer’s disease can be made with a high degree of certainty Using NINCDS-ADRDA criteria, accuracy in autopsy-verified cases is approximately 90% Diagnosis is a 2-step process: –Detection through screening (test vs. family concern) –Confirmation through patient history and physical, caregiver interview, brain imaging, and appropriate laboratory studies McKhann G et al. Neurology. 1984;34:939-944. Kazee AM et al. Alzheimer Dis Assoc Disord. 1993;7:152-164. Ashford JW et al, Psychiaric Annals, 1996;26:262-268.

4. AD is Under-diagnosed Early Alzheimer’s disease is subtle, the diagnosis continues to be missed –it is easy for family members to avoid the problem and compensate for the patient –physicians tend to miss the initial signs and symptoms Less than half of AD patients are diagnosed –Estimates are that 25% to 50% of cases remain undiagnosed –Diagnoses are missed at all levels of severity: mild, moderate, severe No definitive laboratory test for diagnosing AD exists –Efforts to develop biomarkers, early recognition by brain scan have not provided a screening methodology Evans DA. Milbank Quarterly. 1990; 68:267-289

5. Reasons to Diagnose Alzheimer’s Disease Early Social Undiagnosed AD patients face avoidable problems –social, financial Early education of caregivers –how to handle patient (choices, getting started) Advance planning while patient is competent –will, proxy, power of attorney, advance directives Reduce family stress and misunderstanding –caregiver burden, blame, denial Promote safety –driving, compliance, cooking, etc. Patient’s and Family’s right to know –especially about genetic risks Promote advocacy –for research and treatment development

6. Reasons to Diagnose Alzheimer’s Disease Early Medical Early diagnosis and appropriate intervention may lessen disease burden and early treatment may improve overall course substantially –Neurophysiological pathways in patients with AD are still viable and are a target for treatment Specific treatments now available (anti-cholinesterases, memantine) –Improve cognition –Improve function (ADLs) –Delay conversion to AD from Mild Cognitive Impairment –Slow underlying disease process, the sooner the better –Decreased development of behavior problems –Delay nursing home placement, possibly over 20 months –Delay nursing home placement longer if started earlier

7. UNDERLYING CONTINUUM OF ALZHEIMER SEVERITY - progressive disruption of neuroplasticity - (Ashford & Jarvik, 1985; Ashford et al., 1995; Ashford, 2004) ?? unidimensional, but how to measure ?? CROSS-SECTIONAL MEASURES –DEMENTIA SEVERITY (cognitive, ADL) COGNITIVE SCALE SCORE Z-SCORE PRINCIPAL COMPONENT ANALYSIS –BRAIN ATROPHY, DYSFUNCTION –AUTOPSY MEASURES: plaques, tangles –TIME TO DEATH LONGITUDINAL MEASUREMENT –TIME INTO THE DISEASE PROCESS Considerable heterogeneity in disease clinical presentation and brain distribution

8. AAMI / MCI/ early AD -- + -- DEMENTIA ALZHEIMER’S DISEASE CONTINUUM Ashford et al., 1995; Ashford & Schmitt, 2001 derived from CERAD dataset

9. Alzheimer’s Disease Categories NORMAL MILD COGNITIVE IMPAIRMENT (MCI) CRITERIA 1.Memory complaint, preferably corroborated by an informant 2.Objective memory impairment 3.Normal general cognitive function 4.Intact activities of daily living 5.Not demented American Academy of Neurology Petersen et al., 2001 – Neurology 56:1133 Earlier descriptions by: Jonker, Hooyer, 1990 Flicker, Ferris, Reisberg, 1991 Zaudig, 1992 DEMENTIA OF ALZHEIMER TYPE (DSM-IV - APA) Kraemer et al., 2004

10. Yesavavage et al., 2002 Markov Chain model ALZHEIMER’S DISEASE CATEGORIZATION

11. Current Approaches to Early Assessment Genetic vulnerability testing (trait not diagnosis) Vulnerability factors –education, occupation, head injury (not diagnosis) Early concern –Alzheimer Association’s 10 warning signs, ADL dysfunction Dementia severity assessment tools (lack early power) Positive diagnostic tests (too invasive for screening) –CSF – tau levels elevated, amyloid levels low –Brain scan – PET – NFTs: DDNP Amyloid: Thioflavin-S, Congo-red derivatives Need new screening tools (6th vital sign in elderly)

12. Available Short Tests Used for Screening MMSE 10 -- 15 min Too long 7-Minute Screen 7 – 10 min Too complex Clock Drawing Test 2 – 4 min Not sensitive Mini-cog 3 – 5 min To be considered Memory Impairment Screen 4 min To be considered Need to know the cost of administering the test Need to have prospective measurement of sensitivity and specificity for the target population Need to develop progressively better tests

13. Control: What happens without screening? Total Population Risk=P P Have AD No effective intervention Do not have AD P’ Helena Kraemer, 2003

14. Testing: What happens with testing? Total Population No AD AD Unnecessary intervention OKNo effective interventionEffective intervention $ Testing$Testing$ Testing $ Testing $ Intervention Iatragenic Damage?Clinical WashClinical Wash Clinical Gain Major(?) LossMinor (?) LossMinor(?) Loss Major(?) Gain Some gain PP’ Se Se’ SpSp’ Helena Kraemer, 2003

15. $W = Cost–Worthiness Calculation I = incidence (new occurrences each year, by age) $T = cost of test, time to take (Subject, Tester) Se = sensitivity of test = True positive / I Sp = specificity of test = True negative / (1-I) Cost: –$B = benefit of a true positive diagnosis Estimate: (100 years – age ) x $1000 Save $50,000 NH cost / 1year (after treatment cost deduction) –$C = cost of a false positive diagnosis $500 for further evaluation (time, stress of suspecting dementia) –True negative (real peace of mind) (no price) –False negative = false peace of mind (no price) $W = ($B x I x Se) – ($C x (1-I) x (1-Sp)) - $T Kraemer, Evaluating Medical Tests, Sage, 1992

16. JW Ashford, MD PhD, 2003

17. Se, Sp

18. Sp, Se

19. See: Raber et al., 2004

23. (CERAD dataset)

24. JW Ashford, MD PhD, 2003 Mendiondo et al., 2003

25. Issues in Screening ROC analysis provides independent values of test performance –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-benefit must be assessed: –Apply the test cost and the costs of false positive and false negative results –Apply the benefits of correct positive and negative results Alzheimer’s disease is not a dichotomous diagnosis but a continuum –Diagnosis would be better described with a probabilistic statement –Item Response Theory would better calculate probability (Modern Test Theory) Item Response Theory and Factor Analysis allow combination of test components Kraemer, 1992; Ashford & Schmitt, 2001

26. Mini-Mental State Exam items MMSE items Based on Ashford et al., 1989; 1995; applied to CERAD data set

27. See: Hambleton et al., 1990; Ashford & Schmitt, 2001)

28. MMSE Item-Response Analysis

29. Summary Requirements for Screening Test Evaluation Sensitivity, specificity for the population to which test is to be applied –values change with level of disease being screened (must be prospective) Portion of population at risk –Risks according to age, gender, genotype, family hx, education, etc. Cost of test -$1, $10, $100, $1000 –Need brief screen to replace MMSE (ASAP) - $10 Medicare allowance Costs of false positive, false negative tests Benefits of true positive, true negative –Longevity is increasing over time, needs to be factored in. Cascaded tests – preliminary screen, confirmatory exam Longitudinal tests may provide much more reliable information Different tests for clinic (cascaded), research (outcomes) –Clinic: brief screen, brain scan; Research: CSF - is disease stopped? Benefit to society relative to other societal needs.

30. Dementia Screening Test Requirements for the Future For Alzheimer’s disease (other tests for non-AD) –Validated against more stringent tests – brain scans, CSF measures –Specificities and sensitivities valid for comparison with other tests –Item Response Theory analysis of discriminatory power on disability continuum Multiple platforms: –Doctor’s offices –Best if computerized for rapid, objective assessment –World-Wide Web – based testing, –CD-distribution –KIOSK administration – drug stores, shopping malls Very brief (about 1-minute) Multiple test forms –so it can be repeated often, e.g., every 3 months Cost-effective yearly after age 50 –repeatable every 3 months over 65 years of age or with concerns Sensitive to change over time Nominal cost