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, 2005Washington, D.C.

Slides at: www.medafile.com (Dr. Ashford’s lectures)

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

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.

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

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

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

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

Estimate MMSE as a function of time

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Estimated years into illness

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AAMI / MCI/ early AD -- + -- DEMENTIA

ALZHEIMER’S DISEASE CONTINUUM

Ashford et al., 1995; Ashford & Schmitt, 2001

derived from CERAD dataset

Alzheimer’s Disease CategoriesNORMAL

MILD COGNITIVE IMPAIRMENT (MCI) CRITERIA1. Memory complaint, preferably corroborated by an

informant2. Objective memory impairment3. Normal general cognitive function4. Intact activities of daily living5. 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

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Yesavavage et al., 2002Markov Chain model

ALZHEIMER’S DISEASE CATEGORIZATION

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)

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

Control: What happens without screening?

Total Population Risk=P

P

Have ADNo effective intervention

Do not have AD

P’

Helena Kraemer, 2003

Testing: What happens with testing?

Total Population

No ADAD

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

PP’

SeSe’

SpSp’

Helena Kraemer, 2003

$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

JW Ashford, MD PhD, 2003

U.S. mortality rate by age1999 CDC / 2000 census

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Males, 2t = 8.2yrsFemales, 2t = 7.5 yrsAlzheimer incidence

Cost-Worthy Test EvaluationBenefit = $50,000 - 0; False Pos = $500

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050

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Cost-Worthy Test EvaluationBenefit = $50,000 - 0; False Pos = $500

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Dementia rate, for Td = 5 yrs

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mean rateAPOE 4/4APOE 3/4APOE 3/3presenilin

See: Raber et al., 2004

Cost-Worthy Test EvaluationSe=0.9; Sp=0.9

Benefit = $50,000 - 0; False Pos = $500

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ApoE 4/4

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Cost-Worthy Test EvaluationSe=0.9; Sp=0.9

Benefit = $50,000 - 0; False Pos = $500

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Animals named in 1 min (mms>19) - CERAD data set

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Normal Controls, CS = 1, n = 386

Alzheimer patients, CS = 0, n = 380

Animal naming ROCs (AUC 15: 0.74; 30: 0.83; 45: 0.86; 60: 0.87)

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False Positive Rate (%)

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animals in 15 secs

animals in 30 secs

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(CERAD dataset)

BRIEF ALZHEIMER SCREEN (Normal vs Mild AD, MMS>19)

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) (

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animals 1 m AUC = 0.868

animals 30 s AUC = 0.828

MMSE AUC = 0.965

Date+3 Rec AUC = 0.875

BAS AUC = 0.983

JW Ashford, MD PhD, 2003

Mendiondo et al., 2003

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

AD all (easiest to hardest at p=.5)

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DISABILITY ("time-index" year units)

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PENCILAPPL-REPWATCLOCATIONPENY-REPTABL-REPCLOS-ISRIT-HANDCITYFOLD-HLFSENTENCECOUNTYNO-IFSFLOORSEASONYEARPUT-LAPMONTHADDRESSDRAW-PNTDAYSPEL_ALLDATEAPPL-MEMPENY-MEMTABL-MEM

Mini-Mental State Exam items

MMSEitems

Based on Ashford et al., 1989; 1995; applied to CERAD data set

AD all (easiest to hardest at p=.5)

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PENCAPWATCLOCAPETAREDORIGHCITYFOLDSENTCOUNPHRALEVESEASYEARALAPMONTADDRDRAWDAYASPEL_1DATEAPPLPENNTABL

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

AD all

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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.

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