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Phenomics: Phenotype Delineation and Diagnostic Strategies for ARND. By:Larry Burd, Ph.D. North Dakota Fetal Alcohol Syndrome Center 701-777-3683 [email protected] NOSOLOGY. Exposure Detection Classification Diagnosis. Nosological Considerations.

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Phenomics phenotype delineation and diagnostic strategies for arnd l.jpg

Phenomics:Phenotype Delineation and Diagnostic Strategies for ARND

By:Larry Burd, Ph.D.

North Dakota Fetal Alcohol Syndrome Center

701-777-3683

[email protected]


Nosology l.jpg
NOSOLOGY

  • Exposure

  • Detection

  • Classification

  • Diagnosis


Slide3 l.jpg

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 l.jpg
    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 l.jpg

    Detection

    Classification

    FAS

    FAE

    ARND

    ARBD

    FASD

    Affected

    Unaffected

    Phenotype Delineation


    Slide6 l.jpg

    Manifestation of Phenotype

    Phenotype

    Exposure

    PathophysiologyImpairment Disability Death


    Slide7 l.jpg

    Detection Sensitivity

    High

    Low

    Testing & Control Group

    Observation

    & Testing

    Normal

    Tests

    Mortality

    Observation

    Syndromal Severity


    Slide8 l.jpg

    Detection Sensitivity

    Syndrome

    High

    Low

    Severe

    Syndrome

    Mild

    Testing & Control Group

    Increased prevalence of signs

    Observation

    & Testing

    Syndrome and comorbidity

    Normal

    Tests

    Mortality

    Mortality

    Observation

    Typical Syndrome

    NOAEL LOEL TOEL LD - 50

    None Low Typical Lethal

    Exposure (Dose)


    Syndromal variation l.jpg

    Highly Variable Phenotype

    #

    Severe

    Currently Diagnosed

    Classic

    Phenotype Variation

    Syndromal Variation


    Slide10 l.jpg

    Mortality

    ADHD

    Learning

    Disabilities

    Pregnancy

    Losses

    Hearing

    Impairment

    Number of Cases

    Fertility

    Mental

    Disorders

    Visual

    Impairment

    Birth Defects

    Cognitive

    Deficits

    Infectious

    Illness

    Increased

    Severity

    Classic

    Phenotype Variation

    Syndromal Variation

    Highly Variable Phenotype

    CL

    &

    P

    Severe


    Slide11 l.jpg

    Synergistic Effects

    Exposure adverse outcome Susceptibility

    Exposure heart defect brain damage

    Exposure William’s Syndrome + FAS


    Disease status l.jpg
    Disease Status

    +

    -

    Diagnostic

    Status

    *Diagnosis with no exposure; † exposure without diagnosis. TP = true positives; TN = true negatives; FP = false positives; FN = false negatives


    Slide13 l.jpg

    Enviromics

    Exposure

    Dose

    Effect

    Effect Size Outcome

    Genomics

    DNA

    RNA

    Protein

    Metabolites

    Phenotype


    Variance in phenotype vp vg ve l.jpg
    Variance in PhenotypeVp = Vg + Ve

    • Modeling Variance Estimates

      • Vp = Vg + Ve

      • Ve = Vp – Vg

      • Vg = Vp - Ve


    Slide15 l.jpg

    Phenome

    Phenomics

    Severity Comorbidity Age

    vs.

    Criteria

    Phenotype


    Potential etiologies l.jpg
    Potential etiologies

    • Genetic -

    • Infectious -

    • Trauma +


    Adverse outcomes due to prenatal alcohol exposure l.jpg
    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?


    Slide18 l.jpg

    Threshold

    Outcomes

    Exposure Dose


    Slide19 l.jpg

    Hormetic

    Outcomes

    Exposure Dose


    Exposure vs significant exposure l.jpg
    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


    3 9 million births l.jpg
    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 l.jpg
    Prenatal Alcohol Exposure

    • 520,000 pregnancies annually (1)

    • 105,000 high exposure (1)

    • 6% drank in last trimester (2)


    Slide23 l.jpg

    520,000 exposed

    - FAS cases

    500,000 Potential Cases ARND


    Magnitude of effect l.jpg
    Magnitude of effect

    • Height

    • Weight

    • BMI


    Mental disorders adhd 4 l.jpg
    Mental Disorders - ADHD (4)

    • Expected 3.9%

    • Observed 74%


    Slide26 l.jpg

    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 l.jpg
    Prenatal Alcohol Exposure for North Dakota children birth through 21. Course

    Height (5)

    Weight (6)

    BMI


    Change in height percentile rank birth diagnosis l.jpg

    Diagnostic Category for North Dakota children birth through 21.

    Percentile Rank

    FASwMAE

    Part FAS

    No FAS

    Total

    0

    68

    78.16

    83

    91.21

    52

    96.30

    203

    3

    15

    17.24

    3

    3.30

    2

    3.70

    20

    5

    0

    0.00

    1

    1.10

    0

    0.00

    1

    10

    4

    4.60

    4

    4.40

    0

    0.00

    8

    Total

    87

    91

    54

    232

    Missing = 2

    Change in Height Percentile RankBirth - Diagnosis


    Slide29 l.jpg

    Percent of Children who Moved Up in for North Dakota children birth through 21.

    Height Percentile Category from Birth to Diagnosis

    N=232

    %


    Change in weight percentile rank birth diagnosis l.jpg

    Diagnostic Category for North Dakota children birth through 21.

    Percentile Rank

    FASwMAE

    Part FAS

    No FAS

    Total

    0

    90

    72.58

    84

    71.79

    58

    81.69

    232

    < 3

    18

    14.52

    12

    10.26

    6

    8.45

    36

    < 5

    6

    4.84

    6

    5.13

    2

    2.83

    14

    < 10

    10

    8.06

    15

    12.82

    5

    7.04

    30

    Total

    124

    117

    71

    312

    Missing = 3

    Change in Weight Percentile RankBirth - Diagnosis


    Slide31 l.jpg

    Percent of Children who Moved Up in for North Dakota children birth through 21.

    Weight Percentile Category from Birth to Diagnosis

    N=312

    %


    Slide32 l.jpg

    Family History for North Dakota children birth through 21.

    + -

    ADHD

    LD

    Cog Shift

    +

    -

    Prenatal

    Exposure


    Cognition iq prevalence l.jpg
    Cognition: IQ Prevalence for North Dakota children birth through 21.

    < 100 > 85 > 70

    Exposed n =

    Unexposed n =


    Slide35 l.jpg

    “I found one! for North Dakota children birth through 21.

    It’s the only tree here,

    but I expected to find

    a whole forest....”

    Too big

    No leaves

    Smooth

    bark

    Too

    small

    FAS

    Has needles

    House,

    not

    tree

    Trunk too

    thick

    Looks like

    Family

    Has fruit

    Poor soil


    Current diagnosis l.jpg
    Current Diagnosis for North Dakota children birth through 21.

    • Error rate – very high


    Slide37 l.jpg
    Fire for North Dakota children birth through 21.


    Car accident l.jpg
    Car Accident for North Dakota children birth through 21.


    Slide39 l.jpg

    IQ for North Dakota children birth through 21.

    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


    Slide40 l.jpg

    Severity Score for FAS, ARND and Related Disorders for North Dakota children birth through 21.

    By Larry Burd, Ph.D.

    Fetal Alcohol Syndrome Center

    501 N Columbia Road, Grand Forks, ND 58203

    Name Date Age Diagnostic Profile/ARND Score

    FAS Score


    Slide41 l.jpg

    Severity Score for FAS, ARND and Related Disorders for North Dakota children birth through 21.

    By Larry Burd, Ph.D.

    Fetal Alcohol Syndrome Center

    501 N Columbia Road, Grand Forks, ND 58203

    Name Date Age ARND Phenotype Score

    ARND Score


    Recurrence risks l.jpg
    Recurrence Risks for North Dakota children birth through 21.

    • 75% in subsequent exposed pregnancies


    References l.jpg
    References for North Dakota children birth through 21.

    • 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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