Using computers to conduct mass screening for dementia - practical issues and ethics - April 15, 2011 International Association of Geriatrics and Gerontology J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) of Psychiatry & Behavioral Sciences Stanford University Senior Research Scientist Stanford/VA Aging Clinical Research Center, VA Palo Alto Health Care System Palo Alto, California Slides at: www.medafile.com/IAGG2011.ppt
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J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) of Psychiatry & Behavioral Sciences Stanford University Senior Research Scientist
Using computers to conduct mass screening for dementia - practical issues and ethics - April 15, 2011 International Association of Geriatrics and Gerontology. J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) of Psychiatry & Behavioral Sciences Stanford University - PowerPoint PPT Presentation
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Using computers to conduct mass screening for dementia
- practical issues and ethics -
April 15, 2011
International Association of Geriatrics and Gerontology
J. Wesson Ashford, M.D., Ph.D.Clinical Professor (affiliated) of Psychiatry & Behavioral Sciences
Stanford UniversitySenior Research Scientist
Stanford/VA Aging Clinical Research Center, VA Palo Alto Health Care System
Introducing the time-index model of the course of Alzheimer’s disease
Ashford et al., 1995
The best model to fit the progression,both mathematically and biologically,is the Gompertz survival curve (99.7% fit to mean changes over time):S(t) = exp(Ro/alpha *(1- exp (alpha * t)))
(calculated from the CERAD data set)
(Time-Index Scale)
Is it worth screening for memory problems or Alzheimer’s disease?
“If there was treatment for AD, I'd recommend screening, but there is no disease-modifying therapy."
Anonymous Alzheimer expert -2008
“All older adults benefit from memory screening because it detects cognitive problems before memory loss is noticeable.”
Anonymous Alzheimer expert -2008
Healthy Aging, 2008; repost, 2010“Memory Screening: Is it Worth It?”
• Early AD 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%–50% of cases remain undiagnosed– Diagnoses are missed at all levels of severity: mild, moderate, severe
• Undiagnosed AD patients often face avoidable social, financial, and medical problems
• Early diagnosis and appropriate intervention may lessen disease burden– Early treatment may substantially improve overall course
• No definitive laboratory test for diagnosing AD exists– Efforts to develop biomarkers, early recognition by brain scan
Why Memory Screening Is Important to Consider
• Cognitive impairment is disruptive to human well-being and psychosocial function
• Cognitive Impairment is potentially a prodromal condition to dementia and Alzheimer’s disease (AD)
• Dementia is a very costly condition to individuals and society (issue of who is paying for screening, patient care)
• With the aging of the population, there will be a progressive increase in the proportion of elderly individuals in the world (must consider costs to society)
• Screening will lead to better care (more cost-effective care)
No Testing: 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
Factors for Deciding whethera Screening Test is Cost-Effective1) Benefit of a true positive screen2) Benefit of a true negative screen3) Cost of a false positive screen4) Cost of a false negative screen5) Incidence of the disease (in population)6) Test sensitivity (in population)7) Test specificity (in population)8) Test cost
$W = Cost–Worthiness Calculation
$W > ($B x I x Se) – ($C x (1 - I) x (1 - Sp)) - $T• 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 your locale)
– True negative = real peace of mind (no money)• 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)
Kraemer, Evaluating Medical Tests, Sage, 1992
Benefits of Early Alzheimer Diagnosis 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
Benefits of Early Alzheimer Diagnosis Medical
• Early diagnosis and treatment and appropriate intervention may:– improve overall course substantially– lessen disease burden on caregivers / society
• Specific treatments now available (anti-cholinesterases, memantine)– Improve cognition– Improve function (ADLs)– Delay conversion from Mild Cognitive Impairment to AD– 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
Benefits of Early Treatment ofAlzheimer’s Disease
• Neurophysiological pathways in patients with AD are still viable and are a target for treatment
• Opportunity to reduce from a higher level: – Functional decline– Cognitive decline– Caregiver burden
Need to estimate net benefit monetarily
(key factor in determining case for screening)Estimate benefit = (100 years – age ) x $1000
Estimated Age-related Benefitof Early Alzheimer Treatment
Value across continuumValue at transitionValue early
- Sharpness of peak relates to increased sensitivity and specificity - Location of peak relates to point in dementia continuum where recognition would be most beneficial – adjusting sensitivity versus specificity
More specificMore sensitive
Cost of False-Positive Screen
• Referral of normal individual for further testing– (more specific testing)
• Value of individual’s time• Cost of additional testing
• Estimate cost = $500 per false-positive screen
• This does not and should not include the cost of untoward results of misdiagnosis, medication side-effects, or malpractice – quality management should address these issues
Other Benefits and Costs of Screening
• Benefit of true-positive screen = intangible– Peace of mind – Plan further into future
• Cost of false-negative screen = wash– Delay in diagnosis and treatment– No different from current condition
INCIDENCE OF DEMENTIA(Hazard per year)
Based on estimate of 4 million AD patients with dementia in US in 2000, with an incidence that doubles every 5 years, illness duration of 8 years.
U.S. mortality, dementia, MCI rate by age (mortality = 2000 CDC / 2000 census)
JW Ashford, MD PhD, 2003; See: Raber et al., 2004 (Incidence for “a” to “a + 1” year)
The Gompertz survival curve explains 99.7% of male and female mortalityVariance between 30 and 95 y/o in US:
U(t) = Ro * exp (alpha * t)
Relative Risk Factors for Alzheimer’s Disease (after age, early onset genotypes)
• APOE-e4 genotype 1 allele x 4; 2 alleles x 16• Family history of dementia 3.5 (2.6 - 4.6)• Family history - Downs 2.7 (1.2 - 5.7)• Family history - Parkinson’s 2.4 (1.0 - 5.8)• Obese, large abdomen 3.6• Maternal age > 40 years 1.7 (1.0 - 2.9)• Head trauma (with LOC) 1.8 (1.3 - 2.7)• History of depression 1.8 (1.3 - 2.7)• History of hypothyroidism 2.3 (1.0 - 5.4)• History of severe headache 0.7 (0.5 - 1.0)• History of “statin” use 0.3• NSAID use 0.2 (0.05 – 0.83)• Use of NSAIDs, ASA, H2-blockers 0.09
Roca, 1994; ‘t Veld et al., 2001, Breitner et al., 1998, Wolozin et al., 2000
U.S. Alzheimer Incidence
(4 million / 8yr)
02000400060008000
10000120001400016000
50 60 70 80 90 100
Age
# / y
r
male=170,603
female=329,115
JW Ashford, MD PhD, 2003; See: Raber et al., 2004
Zandi et al., JAMA, November 6, 2002—Vol 288, No. 17 p.2127
Dementia rate, assume Td = 5 yrs
0.0001
0.001
0.01
0.1
1
10
100
1000
50 60 70 80 90 100
Age (years)
Haz
ard
/ yea
rmean rate
APOE 4/4 (x7.5)
APOE 3/4 (x2)
APOE 3/3 (x0.6)
Early onset (x200)
Using the Gompertz equationto model rate of dementiaincrease with age:U(t) = Ro * exp (alpha * t)
JW Ashford, MD PhD, 2003; See: Raber et al., 2004
Miech et al., 2002
Cache County, probability of incident dementiaCircles – femalesSquares - malesOpen – ApoE-e44Gray – ApoE-e4/xBlack – ApoE-ex/x
JW Ashford, MD PhD, 2000
U.S. AD Incidence by APOE(proportion of cases)
00.10.20.30.40.50.60.70.80.9
1
50 60 70 80 90 100Age
Prop
ortio
n / Y
ear 4/4
3/43/3
e4/4 – 2% of pop, 20% of casese3/4 - 20% of pop, 40% of casese3/3 - 65% of pop, 35% of cases
Brief Alzheimer Screen (BAS)• Repeat these three words: “apple, table, penny”.• So you will remember these words, repeat them again.• What is today’s date?
• D = 1 if within 2 days.• Spell the word “WORLD” backwards
• S = 1 point for each word in correct order• “Name as many animals as you can in 30 seconds, GO!”
• A = number of animals • “What were the 3 words I asked you to repeat?” (no prompts)
• Alzheimer’s disease, dementia, and memory problems are difficult to detect when they are mild– about 90% missed early – about 25% are still missed late
• There are important accommodations and interventions that should be made when there are cognitive impairments– (like needing glasses or having driving restrictions if you have
vision problems)
Recommendations being considered for mandatory Medicare screen (April, 2011)
1) Ask patient and significant other (if available) if memory is a problem
2) Ask patient and significant other (if available) if remembering to take medications is a problem
3) Ask patient to remember 3 unrelated words, and have the patient repeat the 3 items twice
4) Ask patient the date (note if off by more than 2 days)5) Ask the patient to name as many animals as possible in 1 minute
(note concern if number is below 10)6) Ask the patient to draw a clock (note issues)7) Ask the patient to recall the 3 items that were repeated (note
concern if 2 or 3 items not recalled)8) Evaluate the clinical responses. If problems noted, consider
possible explanations or need for further evaluation
There is considerable resistance to implementation of clinical screening
1) Clinicians are concerned that they don’t have time to screen
2) Certain organizations recommend use of warning signs, which have not been studied or ever shown to be effective for recognizing early cases
3) There needs to be a technique for easy recognition of memory problems in an at-risk individual
4) Audience memory screening is available5) Memory tests are available on the WEB6) Computerized testing is more effective and efficient
Issues for Memory Screening• Memory (neuroplasticity) is the fundamental deficit of
Alzheimer’s disease
• Current testing for memory problems is based on having a tester sit in front of a subject for a prolonged period of time and administer unpleasant tests
• Testing must be – Inexpensive (minimal need for administrator)– Fun (so people will return for frequent testing)– More precise, reliable, and valid
• To improve sensitivity• To improve specificity
Audience Screening: CONTINUOUS RECOGNITION TEST
• Presentation of complex pictures (that are easily remembered normally) are useful for detecting memory difficulties
• Testing memory using a pictures approach needs standardization for population use
• Picture memory is less affected by education• Picture memory can be tested by computer• Audiences can be shown slide presentations
Answer Sheet for Memory Screening (back of sheet)Carefully look at each picture. If you see a picture that you have seen before, mark the circle next to the number of the repeat picture. For the main test, you will see 50 pictures. Each picture is numbered. The pictures will stay on the screen for 5 seconds. 25 pictures are new, 25 pictures are repeated.
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THE END
Please note the number on your answer sheet, then hand it in.
MEMTRAX Memory Test
116 subjects – mostly elderly normals, some young, some dementia patientsFalse positive errors (false recognition) – 33(64);6(58);47(27)—4,18,23,34(1);1,2,8(0)False negative errors (failure to recognize) – 35(33);27(20);5(16)—32(4);24(3);45(3)
• (false negative responses = failure to recognize/recall repeat picture)(false negative responses = failure to recognize/recall repeat picture)
True Negative Performance
y = -0.0352x + 25.564R2 = 0.039
y = -0.0597x + 27.24R2 = 0.141
1213141516171819202122232425
40.0 50.0 60.0 70.0 80.0 90.0 100.0
Age (years)
Num
ber C
orre
ct
Male true-
Female true-
Linear (Male true-)
Linear (Female true-)
True Positive Performance
y = -0.0438x + 27.029R2 = 0.0617
y = -0.0418x + 26.746R2 = 0.0605
1213141516171819202122232425
40.0 50.0 60.0 70.0 80.0 90.0 100.0
Age (years)
Num
ber C
orre
ct
Male true+
Female true+
Linear (Male true+)
Linear (Female true+)
False Positives (incorrect guesses)
y = -0.0935x + 3.7674R2 = 0.0153
y = -0.021x + 2.5605R2 = 0.0007
0
2
4
6
8
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6 8 10 12 14 16 18 20
Education (years)
Num
ber W
rong
Male False+
Female False+
Linear (Male False+)
Linear (Female False+)
False Negatives (memory failures)
y = -0.0042x + 1.4457R2 = 3E-05
y = -0.0398x + 1.255R2 = 0.02
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Education (years)
Num
ber W
rong
Male False-
Female False-
Linear (Male False-)
Linear (Female False-)
The relationship between discriminability (d ) and age ′on the audience-based continuous recognition test of memory for 868 individuals with all information.
The relationship between discriminability performance (d ) and age in 868 individuals on ′the continuous recognition test of memory.
The relationship between discriminability performance (d ) and age in 868 individuals on ′the continuous recognition test of memory.
The relationship between discriminability index (d ) and education in 868 individuals on the ′continuous recognition test of memory.
*
The relationship between the number of intervening items (between initial and first repeat presentations) and percent correct on those items on the continuous recognition test of memory.
The relationship between percent correct and item repetition in 868 individuals on the continuous recognition test of memory.
WEB-based ScreeningOn-line Testing
• Same test paradigm as Audience Screening• Testing can be faster – 1-2 minutes for 50 image• Many different variations of the test can be given• Other aspects of cognition can be tested• Test can be repeated several times to decrease variance• Test can be taken over time to detect changes• Improved anonymity to protect private information
MEMTRAX - Memory Test(to detect AD onset)
• New test to screen patients for AD: – World-Wide Web – based testing– CD-distribution– KIOSK administration (grocery stores, drug stores)
• Determine level of ability / impairment• Test takes 2 to 3 minutes• Test can be repeated often (e.g., weekly, quarterly)• Any change over time can be detected
MemTrax WEB Testing• Blueberry Study
– 12 subjects – no health problems reported
– Mean age = 49.3 + 11.7 (range 31-68)
– 2 weeks of testing (5 days each week)
– 11 different tests
– 14 to 18 administrations per subject
d' by Test #
0.0000
0.5000
1.0000
1.5000
2.0000
2.5000
3.0000
3.5000
4.0000
4.5000
0 2 4 6 8 10 12
Test #
d'
d' by Agey = 0.0076x + 2.8553R2 = 0.0219
0.0000
0.5000
1.0000
1.5000
2.0000
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3.0000
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30 35 40 45 50 55 60 65 70
Age
d'
d' by Test Ordery = -0.0067x + 3.2933R2 = 0.0032
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Reaction Time by Test #
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ect r
eacti
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mes
Reaction Time by Agey = 1.3554x + 622.79R2 = 0.0276
0
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30 35 40 45 50 55 60 65 70
Age
Corr
ect r
eacti
on ti
mes
Reaction Time by Test Order y = -0.4084x + 693.39R2 = 0.0005
Correlation coefficient with n-2 (9 for 11 subjects) degrees of freedom is: significant at p < .10 level with a value of at least 0.521, p < .05 at 0.602, and p < .01 at 0.735.
Correlations significant at the .10, .05 and .01 level are shown in red, blue, and green type respectively.
BlueBerry Study – MemTrax – correlation analyses
Reaction Time as a Function of Hearing y = -1.4941x + 870.94R2 = 0.3873
500.0
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Offline HAP
Cor
rect
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ctio
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(mse
cs)
Conclusions• The ethical concerns of values and harms must be estimated as costs
and benefits• Incidence, costs, and test accuracy each play a role in determining
whether screening is justified• Calculations show that screening for memory problems is justified
under specific circumstances, age, and risks• Memory can be measured in mass settings using an audience- based
system or web administration over the internet• The remaining question is whether health systems are prepared to
provide the care that will improve the lives of those affected• In the future, the incidence is climbing, so the problem may be much
worse. Will future treatments be better? • Legislation is needed to require training of clinicians to properly
diagnose, treat, and manage dementia patients and for mandating appropriate reimbursements of clinicians for their work
• Screening tests are ready for widespread implementation