1 / 30

Improving Alzheimer’s Disease Screening: Statistical Insights and Diagnostic Challenges

This presentation by Dr. J. Wesson Ashford and Dr. Helena C. Kraemer delves into the statistical issues surrounding the development of screening tests for Alzheimer's disease. It emphasizes the need for annual assessments and the importance of early detection, as over 50% of cases remain undiagnosed until moderate stages. The presentation discusses the two-step diagnostic process utilizing NINCDS-ADRDA criteria, the need for biomarkers, and the social and medical reasons for early diagnosis. The ultimate goal is to promote advocacy, improve cognition, and reduce caregiver burdens through timely interventions.

lawrence-acosta
Télécharger la présentation

Improving Alzheimer’s Disease Screening: Statistical Insights and Diagnostic Challenges

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Statistical Issues for DevelopingAlzheimer 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)

  2. Screening for Alzheimer’s DiseaseWhat 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. ALZHEIMER’S DISEASE CONTINUUM derived from CERAD dataset AAMI / MCI/ early AD -- + -- DEMENTIA Ashford et al., 1995; Ashford & Schmitt, 2001

  9. Alzheimer’s Disease Categories NORMAL MILD COGNITIVE IMPAIRMENT (MCI) CRITERIA • Memory complaint, preferably corroborated by an informant • Objective memory impairment • Normal general cognitive function • Intact activities of daily living • 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. ALZHEIMER’S DISEASE CATEGORIZATION Yesavavage et al., 2002 Markov Chain model

  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 TestsUsed 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’ P Have AD No effective intervention Do not have AD Helena Kraemer, 2003

  14. Testing: What happens with testing? Total Population P’ P AD No AD Se Se’ Sp’ Sp Unnecessary intervention OK No effective intervention Effective intervention $ Testing $Testing $ Testing $ Testing $ Intervention $ Intervention Iatragenic Damage? Clinical Wash Clinical Wash Clinical Gain Major(?) Loss Minor (?) Loss Minor(?) Loss Major(?) Gain Some gain 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 Se, Sp

  18. Sp, Se

  19. See: Raber et al., 2004

  20. (CERAD dataset)

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

  22. 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

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

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

  25. MMSE Item-Response Analysis

  26. 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.

  27. 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

More Related