Use of Biomarkers in Epidemiology
Transcript of Use of Biomarkers in Epidemiology
![Page 1: Use of Biomarkers in Epidemiology](https://reader031.fdocuments.net/reader031/viewer/2022012412/616ca7497261ec7dd40718d5/html5/thumbnails/1.jpg)
Potential Roles and Limitations of
Biomarkers in Alzheimer’s Disease
Richard Mayeux, MD, MSc
Columbia University
![Page 2: Use of Biomarkers in Epidemiology](https://reader031.fdocuments.net/reader031/viewer/2022012412/616ca7497261ec7dd40718d5/html5/thumbnails/2.jpg)
Biomarkers and Disease
– Natural history
– Risk prediction
– Phenotype definition
– Clinical and biological heterogeneity
– Diagnostic or screening tests
– Response to treatment
– Prognosis
![Page 3: Use of Biomarkers in Epidemiology](https://reader031.fdocuments.net/reader031/viewer/2022012412/616ca7497261ec7dd40718d5/html5/thumbnails/3.jpg)
Use of Biomarkers in Epidemiology and
Clinical Medicine
Traditional
Exposure Disease
Biological or Molecular Epidemiology
Markers of Exposure Biomarkers of Disease
Exposure dose biological effect
Altered clinical prognosis
structure/ diagnosis
function
![Page 4: Use of Biomarkers in Epidemiology](https://reader031.fdocuments.net/reader031/viewer/2022012412/616ca7497261ec7dd40718d5/html5/thumbnails/4.jpg)
Disease Pathway
etiology
pathogenesis
induction latency disease
detection
Alzheimer
Diseasebiomarkers
risk factors screening & diagnosis prognosis
![Page 5: Use of Biomarkers in Epidemiology](https://reader031.fdocuments.net/reader031/viewer/2022012412/616ca7497261ec7dd40718d5/html5/thumbnails/5.jpg)
Steps to Develop Biomarker
selection of type: risk factor vs. disease surrogate
validity of relation to disease
field methods
dose-response
modifiers
sensitivity & specificity
population variation
![Page 6: Use of Biomarkers in Epidemiology](https://reader031.fdocuments.net/reader031/viewer/2022012412/616ca7497261ec7dd40718d5/html5/thumbnails/6.jpg)
Risk or Predictors
![Page 7: Use of Biomarkers in Epidemiology](https://reader031.fdocuments.net/reader031/viewer/2022012412/616ca7497261ec7dd40718d5/html5/thumbnails/7.jpg)
Temporal Relationship
Past Present Future
Case-control
Biomarker
Disease
Cohort Study
“odds of exposure”
“risk of disease”
Biomarker
Disease
![Page 8: Use of Biomarkers in Epidemiology](https://reader031.fdocuments.net/reader031/viewer/2022012412/616ca7497261ec7dd40718d5/html5/thumbnails/8.jpg)
Exposure-Biomarker-Disease
Association
1. IM1 D
2. IM1 D
IM2
One or two intermediate
biomarkers sufficient to
cause disease
3. E1 IM1 D
E2 IM2
4. E1 IM1 D
E2 IM2
5. E U D
IM1Exposures mediated via intermediate
biomarker(s) or exposure is related to an
unknown event associated with biomarker
![Page 9: Use of Biomarkers in Epidemiology](https://reader031.fdocuments.net/reader031/viewer/2022012412/616ca7497261ec7dd40718d5/html5/thumbnails/9.jpg)
Strategy to Validate Biomarkers of Risk
• Select candidates relevant to disease pathway
• Identify and quantitate the association between the maker and the disease
• For intermediate markers consider attributable proportion
Disease
Biomarker yes no
Present A B
Absent C D
Sensitivity (S) = A/A+C
RR= [A/(A+B)]/[C/(C+D)]
Attributable proportion =
S(1-1/RR)
![Page 10: Use of Biomarkers in Epidemiology](https://reader031.fdocuments.net/reader031/viewer/2022012412/616ca7497261ec7dd40718d5/html5/thumbnails/10.jpg)
Relation Between Predictive Value and
Frequency of Biological Marker
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 40 50 60 70 80 90 100
99,50
90,90
70,70
50,99
50,50
sensitivity
specificity
frequency
![Page 11: Use of Biomarkers in Epidemiology](https://reader031.fdocuments.net/reader031/viewer/2022012412/616ca7497261ec7dd40718d5/html5/thumbnails/11.jpg)
Screening & Diagnosis
![Page 12: Use of Biomarkers in Epidemiology](https://reader031.fdocuments.net/reader031/viewer/2022012412/616ca7497261ec7dd40718d5/html5/thumbnails/12.jpg)
Sensitivity = a/a+c (true positives/patients)
Specificity = d/b+d (true negatives/healthy)
*PPV = a/a+b (true positives/trait present)
*NPV = d/c+d (true negatives/trait absent)
*Prior probability = a+c/N (patients/total population)
Diagnostic & Screening Tests
![Page 13: Use of Biomarkers in Epidemiology](https://reader031.fdocuments.net/reader031/viewer/2022012412/616ca7497261ec7dd40718d5/html5/thumbnails/13.jpg)
0
20
40
60
80
100
0 20 40 60 80 100
predictive values
prevalence or prior probability
NPVPPV
Relation Between Prior Probability and
Predictive Values for a Test (90/90)
![Page 14: Use of Biomarkers in Epidemiology](https://reader031.fdocuments.net/reader031/viewer/2022012412/616ca7497261ec7dd40718d5/html5/thumbnails/14.jpg)
Evaluation of Diagnostic Tests
• Receiver operating characteristic ( ROC)
– Estimates probabilities of decision outcomes
– Provides an index of the accuracy decision
criterion
– A measure of detection and misclassification
– Efficacy = practical (or “added”) value
![Page 15: Use of Biomarkers in Epidemiology](https://reader031.fdocuments.net/reader031/viewer/2022012412/616ca7497261ec7dd40718d5/html5/thumbnails/15.jpg)
Utility of APOE Genotype in Diagnosis
of Alzheimer’s Disease
0
20
40
60
80
100
0 20 40 60 80 100
APOE
NINCDS-ADRDA
combined
sensitivity
false positive rate
![Page 16: Use of Biomarkers in Epidemiology](https://reader031.fdocuments.net/reader031/viewer/2022012412/616ca7497261ec7dd40718d5/html5/thumbnails/16.jpg)
Requirements for Screening Tests
• Test must be quick, easy and inexpensive
• Test must be safe, acceptable to persons screened
and physicians or health care workers screening
• Sensitivity, specificity and predictive values must
be known and acceptable to medical community
• Adequate follow-up for screened positives with
and without disease
![Page 17: Use of Biomarkers in Epidemiology](https://reader031.fdocuments.net/reader031/viewer/2022012412/616ca7497261ec7dd40718d5/html5/thumbnails/17.jpg)
Prognosis
• Same rules apply:
– Sensitivity and specificity
– Validity of outcome and exclusion of
confounders
– Relation between stage of disease and marker
![Page 18: Use of Biomarkers in Epidemiology](https://reader031.fdocuments.net/reader031/viewer/2022012412/616ca7497261ec7dd40718d5/html5/thumbnails/18.jpg)
Biomarkers: What Is Needed?
Administrative
support
Study design,
implementation, coordination
& analysis
Biostatistics
Field workExposure
Assessment
Effects
Assessment
Interviewers
Specimen
collectors
Field lab
Data management
Laboratory Manager
Technicians
Specimen banker
Registry
Laboratory
Specimen banker
Collaborating investigators,
institutions, etc
Registry and database
![Page 19: Use of Biomarkers in Epidemiology](https://reader031.fdocuments.net/reader031/viewer/2022012412/616ca7497261ec7dd40718d5/html5/thumbnails/19.jpg)
Measurement Errors
• Source
– Donor problem
– Collection equipment
– Technician
– Transport/handling
– Storage
– Receipt and control
errors
(e.g.Transcription)
• Solutions
– Procedures manual
– Document storage
– Monitor specimens for
degredation
– Maintain records
– Quality control
program
![Page 20: Use of Biomarkers in Epidemiology](https://reader031.fdocuments.net/reader031/viewer/2022012412/616ca7497261ec7dd40718d5/html5/thumbnails/20.jpg)
Bias
• Sources
– Specimen unrelated to
exposure or disease
– Differential availability
related to exposure or
disease
– Specimen acquisition,
storage, analysis or
procedures related to
exposure or disease
• Solutions
– High response rate rate
– Document procedures to monitor selection bias
– Keep track of specimen usage
– Aliquot & use small portions
– Use reviewed by objective panel
![Page 21: Use of Biomarkers in Epidemiology](https://reader031.fdocuments.net/reader031/viewer/2022012412/616ca7497261ec7dd40718d5/html5/thumbnails/21.jpg)
Confounding
• Sources
– Failure to identify
potential intermediate
factors or related
biomarkers (e.g. BMI,
use of laboratory kits)
– Failure to adjust for
confounders in the
analyses
• Solutions
– Use data on confounders in designing study
– Collect relevant data on acquisitions, transport, storage and laboratory personnel changes
– Discuss confounders with biostatistician
![Page 22: Use of Biomarkers in Epidemiology](https://reader031.fdocuments.net/reader031/viewer/2022012412/616ca7497261ec7dd40718d5/html5/thumbnails/22.jpg)
Advantages
• objective
• precision
• reliable/valid
• less biased
• disease mechanism
• homogeneity of
risk or disease
status
Disadvantages
• timing
• expensive
• storage
• laboratory errors
• normal range
• statistics
• ethical
responsibility
Biomarkers
![Page 23: Use of Biomarkers in Epidemiology](https://reader031.fdocuments.net/reader031/viewer/2022012412/616ca7497261ec7dd40718d5/html5/thumbnails/23.jpg)
It’s the Controls, Stupid!