Phenomics: Phenotype Delineation and Diagnostic Strategies for ARND

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PhenomicsPhenotype Delineation and Diagnostic
Strategies for ARND

• ByLarry Burd, Ph.D.
• North Dakota Fetal Alcohol Syndrome Center
• 701-777-3683
• laburd_at_medicine.nodak.edu

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NOSOLOGY

• Exposure
• Detection
• Classification
• Diagnosis

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Nosological Considerations

• Types of Pathological Conditions
• Syndrome cluster of symptoms
• Disorder cluster of symptoms with specific
  diagnostic criteria
• Disease cluster of symptoms with single, known
  etiology
• Discrete Mental Disorders vs. Symptom Clusters
  Continuum.

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Preferred Performance Characteristics

1. Captures many most cases
2. Reflects understanding of comorbidity
3. Does not exert a protective effect
4. Easy to implement
5. Leads to prevention of recurrence
6. Protects mother
7. Decreases secondary disability
8. Leads to appropriate interventions

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Phenotype Delineation

• Detection
• Classification
• FAS
• FAE
• ARND
• ARBD
• FASD

• Affected
• Unaffected

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Manifestation of Phenotype
Phenotype
Exposure
Pathophysiology Impairment Disability Death
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Detection Sensitivity
High
Low
Testing Control Group
Observation Testing
Normal Tests
Mortality
Observation
Syndromal Severity
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Detection Sensitivity
Syndrome
High
Low
Severe Syndrome Mild
Testing Control Group
Observation Testing
Increased prevalence of signs
Syndrome and comorbidity
Normal Tests
Mortality
Observation
Mortality
Typical Syndrome
NOAEL LOEL TOEL
LD - 50 None Low
Typical Lethal
Exposure (Dose)
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Syndromal Variation
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Syndromal Variation
Highly Variable Phenotype
CL P
Severe
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Synergistic Effects
Exposure adverse outcome
Susceptibility Exposure heart defect
brain damage Exposure Williams
Syndrome FAS
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Disease Status
-
True positives TPTNphenocopies _____ 100 False positives FPFNphenocopies ____ 100
False Negatives FNTNphenocopies _____ 100 True negatives FPTPphenocopies _____ 100
-
Diagnostic Status
Diagnosis with no exposure exposure without
diagnosis.
TP true positives TN true negatives
FP false positives FN false negatives
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Enviromics Exposure Dose Effect Effect Size
Outcome
Genomics DNA RNA Protein Metabolites
Phenotype
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Variance in Phenotype Vp Vg Ve

• Modeling Variance Estimates
• Vp Vg Ve
• Ve Vp Vg
• Vg Vp - Ve

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Phenome Phenomics Severity
Comorbidity Age
vs. Criteria Phenotype
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Potential etiologies

• Genetic -
• Infectious -
• Trauma

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Adverse Outcomes Due to Prenatal Alcohol Exposure

• Yes or No
• Did mom drink?
• Did she drink enough?
• Abnormal signs or disorders?
• Is Alcohol a contributor to outcome?
• Is Alcohol casual?

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Threshold
Outcomes
Exposure Dose
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Hormetic
Outcomes
Exposure Dose
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Exposure vs. Significant Exposure

• NOEL
• No Observable Effect Level
• LOAEL
• Lowest Observable Adverse Effect Level
• TAEL
• Typical Adverse Effect Level 50 with adverse
  outcome at exposure level
• LD 50
• Lethal Dose for 50 exposed

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3.9 Million Births

• 1,560,000 Exposed
• 137,000 Frequent heavy drinking
• 39,000 FAS-RD
• The National Center on Addiction and Substance
  Abuse, 1999

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Prenatal Alcohol Exposure

• 520,000 pregnancies annually (1)
• 105,000 high exposure (1)
• 6 drank in last trimester (2)

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• 520,000 exposed
• - FAS cases
• 500,000 Potential Cases ARND

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Magnitude of effect

• Height
• Weight
• BMI

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Mental Disorders - ADHD (4)

• Expected 3.9
• Observed 74

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Prenatal Alcohol ExposureCourse

• Height (5)
• Weight (6)
• BMI

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Change in Height Percentile RankBirth - Diagnosis
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Percent of Children who Moved Up in Height
Percentile Category from Birth to Diagnosis
N232

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Change in Weight Percentile RankBirth - Diagnosis
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Percent of Children who Moved Up in Weight
Percentile Category from Birth to Diagnosis
N312

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Family History
-
ADHD LD Cog Shift
-
Prenatal Exposure
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Cognition IQ Prevalence

• lt 100 gt 85 gt 70
• Exposed n
• Unexposed n

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Controls 1 IQ gt85 or gt70
PAE 2 PAE
PAE-FH 3 PAE Family History
PAE-FH Affected sib 4 PAE Family History Affected Sibling
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Current Diagnosis

• Error rate very high

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Fire
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Car Accident
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IQ
Below Average Borderline Mild Moderate Severe
Due to Prenatal Alcohol Exposure?
Yes No Uncertain
IQ AB or Age AB
Yes No Uncertain
ADHD
Rating (P T) TOVA N of 1
Yes No Uncertain
Learning Disorders
Yes No Uncertain
IQ - Achiv 20
Mental Disorders
Diagnoses
Yes No Uncertain
Neuropsychological
Impairments
Yes No Uncertain
Imaging
CTFMRI MRIPET EEGMEG Spect
Yes No Uncertain
Other findings
Findings
Yes No Uncertain
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Severity Score for FAS, ARND and Related
Disorders By Larry Burd, Ph.D. Fetal Alcohol
Syndrome Center 501 N Columbia Road, Grand Forks,
ND 58203 Name Date Age Diagnostic
Profile/ARND Score
Growth FAS Phenotype Score
Height 10 height percentile
Weight 10 growth percentile
Head circumference 10 head circumference percentile

(Diagnostic Profile)
Number of facial features
Number of anomalies

Comorbid neuropsychiatric conditions __________ x 2
IQ (Select only one)
lt85 Score 4 lt70 Score 8 lt50 Score 10
Sleep (Select only one)
lt6 consecutive hours Score 1 lt4 consecutive hour Score 5 lt2 consecutive hours Score 10
FAS Score
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Severity Score for FAS, ARND and Related
Disorders By Larry Burd, Ph.D. Fetal Alcohol
Syndrome Center 501 N Columbia Road, Grand Forks,
ND 58203 Name Date Age ARND Phenotype
Score
Comorbid neuropsychiatric conditions __________ x 2
IQ (Select only one) lt85 Score 4 lt70 Score 8 lt50 Score 10
Sleep (Select only one) lt6 consecutive hours Score 1 lt4 consecutive hour Score 5 lt2 consecutive hours Score 10
10 (Communications score ? 10)
10 (Daily living score ? 10)
10 (Socialization score ? 10)
10 (Motor skills score ? 10)

Services Foster Care of placements __________ x 3
Inpatient hospital care of weeks in last year __________
Criminal justice of months on probation or incarceration in last year __________
In Special education of hours per day __________
Residential care of months in last year __________
ARND Score
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Recurrence Risks

• 75 in subsequent exposed pregnancies

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References

• CDC
• Whitehead
• Burd L, Klug M, Martsolf J, Kerbeshian J. Fetal
  alcohol syndrome Neuropsychiatric Phenomics.
  Neurotoxicol Teratol (in press) 2003.
• Klug MG, Burd L. Fetal alcohol syndrome
  prevention Annual and cumulative cost savings.
  Neurotoxicol Teratol (in press) 2003.
• Day
• Burd L, Klug MG, Martsolf J, Ebertowski M. Body
• Mental Disorders in FAS