Phenomics: Phenotype Delineation and Diagnostic Strategies for ARND By:Larry Burd, Ph.D. North Dakota Fetal Alcohol Syndrome Center 701-777-3683 laburd@medicine.nodak.edu

NOSOLOGY Exposure Detection Classification Diagnosis

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.

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

Phenotype Delineation Detection Classification FAS FAE ARND ARBD FASD Affected Unaffected

Manifestation of Phenotype Exposure Pathophysiology Impairment Disability Death

Testing & Control Group Detection Sensitivity High Low Testing & Control Group Observation & Testing Normal Tests Mortality Observation Syndromal Severity

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)

Syndromal Variation Highly Variable Phenotype # Severe Phenotype Variation # Highly Variable Phenotype Classic Severe Currently Diagnosed

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

Synergistic Effects Exposure adverse outcome Susceptibility Exposure heart defect brain damage Exposure William’s Syndrome + FAS

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

Enviromics Exposure Dose Effect Effect Size Outcome Genomics DNA RNA Protein Metabolites Phenotype

Variance in Phenotype Vp = Vg + Ve Modeling Variance Estimates Vp = Vg + Ve Ve = Vp – Vg Vg = Vp - Ve

Severity Comorbidity Age Phenome Phenomics Severity Comorbidity Age vs. Criteria Phenotype

Potential etiologies Genetic - Infectious - Trauma +

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?

Threshold Outcomes Exposure Dose

Hormetic Outcomes Exposure Dose

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

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

Prenatal Alcohol Exposure 520,000 pregnancies annually (1) 105,000 high exposure (1) 6% drank in last trimester (2)

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

Magnitude of effect Height Weight BMI

Mental Disorders - ADHD (4) Expected 3.9% Observed 74%

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

Prenatal Alcohol Exposure Course Height (5) Weight (6) BMI

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

Percent of Children who Moved Up in Height Percentile Category from Birth to Diagnosis N=232 %

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

Percent of Children who Moved Up in Weight Percentile Category from Birth to Diagnosis N=312 %

Family History + - ADHD LD Cog Shift + - Prenatal Exposure

Cognition: IQ Prevalence < 100 > 85 > 70 Exposed n = Unexposed n =

Controls 1 IQ >85 or >70 PAE 2 + PAE PAE-FH 3 + PAE – Family History PAE-FH + Affected sib 4 Affected Sibling

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

Current Diagnosis Error rate – very high

Fire

Car Accident

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

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

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

Recurrence Risks 75% in subsequent exposed pregnancies

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