Phenomics: Phenotype Delineation and Diagnostic Strategies for ARND

1. 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

2. NOSOLOGY • Exposure • Detection • Classification • Diagnosis

3. 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.

4. 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

5. Detection Classification FAS FAE ARND ARBD FASD Affected Unaffected Phenotype Delineation

6. Manifestation of Phenotype Phenotype Exposure PathophysiologyImpairment Disability Death

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

8. 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)

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

10. 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

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

12. Disease Status + - Diagnostic Status *Diagnosis with no exposure; † exposure without diagnosis. TP = true positives; TN = true negatives; FP = false positives; FN = false negatives

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

14. Variance in PhenotypeVp = Vg + Ve • Modeling Variance Estimates • Vp = Vg + Ve • Ve = Vp – Vg • Vg = Vp - Ve

15. Phenome Phenomics Severity Comorbidity Age vs. Criteria Phenotype

16. Potential etiologies • Genetic - • Infectious - • Trauma +

17. 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?

18. Threshold Outcomes Exposure Dose

19. Hormetic Outcomes Exposure Dose

20. 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

21. 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

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

23. 520,000 exposed - FAS cases 500,000 Potential Cases ARND

24. Magnitude of effect • Height • Weight • BMI

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

26. 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

27. Prenatal Alcohol ExposureCourse Height (5) Weight (6) BMI

28. Diagnostic Category 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

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

30. Diagnostic Category 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

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

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

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

35. “I found one! 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

36. Current Diagnosis • Error rate – very high

37. Fire

38. Car Accident

39. 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

40. 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 FAS Score

41. 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 ARND Score

42. Recurrence Risks • 75% in subsequent exposed pregnancies

43. 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