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Phenomics: Phenotype Delineation and Diagnostic Strategies for ARND
By:Larry Burd, Ph.D. North Dakota Fetal Alcohol Syndrome Center
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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
Captures many – most cases Reflects understanding of comorbidity Does not exert a protective effect Easy to implement Leads to prevention of recurrence Protects mother Decreases secondary disability 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
Exposure Pathophysiology Impairment Disability Death
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Testing & Control Group
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 Increased prevalence of signs Syndrome and comorbidity Observation & Testing Normal Tests Mortality Mortality Typical Syndrome Observation NOAEL LOEL TOEL LD - 50 None Low Typical Lethal Exposure (Dose)
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Syndromal Variation Highly Variable Phenotype # Severe
Phenotype Variation # Highly Variable Phenotype Classic Severe Currently Diagnosed
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Highly Variable Phenotype
Syndromal Variation Highly Variable Phenotype CL & P Number of Cases Classic ADHD Hearing Impairment Cognitive Deficits Learning Disabilities Mental Disorders Infectious Illness Mortality Pregnancy Losses Fertility Birth Defects Increased Severity Visual Phenotype Variation Severe
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Synergistic Effects Exposure adverse outcome Susceptibility
Exposure heart defect brain damage Exposure William’s Syndrome + FAS
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Disease Status Diagnostic Status True positives = False positives =
+ - True positives = TP+TN+phenocopies* _____ 100% False positives = FP+FN+phenocopies† ____ False Negatives= FN+TN+phenocopies* _____ True negatives = FP+TP+phenocopies† _____ + - 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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Severity Comorbidity Age
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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The National Center on Addiction and Substance Abuse, 1999
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, 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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Costs of health care for FAS and related comorbid conditions for North Dakota children birth through 21. (4) Cumulative Cost Savings Average Extra from Preventing One Case per Year Yearly Cost Yearly Cost After 10 Years After 20 Years FAS $2,842 $2,342 $128,810 $491,820 ADHD $649 $154 $8,470 $32,340 Learn Dis $1,302 $806 $44,330 $169,260 Develop Dis $2,286 $1,797 $98,835 $377,370 ODD $1,377 $883 $48,565 $185,430 Seizures $2,181 $1,689 $92,895 $354,690 FAS = Fetal Alcohol Syndrome ADHD = Attention Deficit Hyperactivity Disorder Learn Dis = Learning Disabilities Develop Dis = Developmental Disorders ODD = Oppositional Defiant Disorder
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Prenatal Alcohol Exposure Course
Height (5) Weight (6) BMI
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Change in Height Percentile Rank Birth - Diagnosis
Diagnostic Category Percentile Rank FASwMAE Part FAS No FAS Total 68 78.16 83 91.21 52 96.30 203 3 15 17.24 3.30 2 3.70 20 5 0.00 1 1.10 10 4 4.60 4.40 8 87 91 54 232 Missing = 2
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Percent of Children who Moved Up in
Height Percentile Category from Birth to Diagnosis N=232 %
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Change in Weight Percentile Rank Birth - Diagnosis
Diagnostic Category Percentile Rank FASwMAE Part FAS No FAS Total 90 72.58 84 71.79 58 81.69 232 < 3 18 14.52 12 10.26 6 8.45 36 < 5 4.84 5.13 2 2.83 14 < 10 10 8.06 15 12.82 5 7.04 30 124 117 71 312 Missing = 3
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Percent of Children who Moved Up in
Weight Percentile Category from Birth to Diagnosis N=312 %
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Family History + - ADHD LD Cog Shift + - Prenatal Exposure
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Cognition: IQ Prevalence
< > 85 > 70 Exposed n = Unexposed n =
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Controls 1 IQ >85 or >70 PAE 2 + PAE PAE-FH 3 + PAE – Family History PAE-FH + Affected sib 4 Affected Sibling
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Too big Has fruit Too small Poor soil Smooth bark No leaves Has needles Looks like Family FAS “I found one! It’s the only tree here, but I expected to find a whole forest....” Trunk too thick House, not tree
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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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Due to Prenatal Alcohol Exposure?
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 IQ - Achiv = 20 Yes No Uncertain 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) <85 Score 4 <70 Score 8 <50 Score 10 Sleep (Select only one) <6 consecutive hours Score 1 <4 consecutive hour Score 5 <2 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) <85 Score 4 <70 Score 8 <50 Score 10 Sleep (Select only one) <6 consecutive hours Score 1 <4 consecutive hour Score 5 <2 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
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