Phenomics By: Larry Burd, Ph.D. Director, North Dakota Fetal Alcohol Syndrome Center University of North Dakota, School of Medicine and Health Sciences Grand Forks, ND

Study of Outcomes

Detection Classification

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

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.

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

Manifestation of Phenotype Exposure Pathophysiology Impairment Disability Death

Syndromal Severity Alcohol Binges Total Dose Days Exposed Genetics Age 5 - 10 - 15 - 20 - 25 - 30 - 35 - Alcohol Binges Total Dose Days Exposed Genetics Age Education Diet Smoking Previously Affected Child Maternal Causal Chain Cumulative Affect Causal Pathway

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

Fetal Alcohol Syndrome Causal Chain Elements Effect Size Alcohol >14 oz + + + + + + + + + Smoking >1 pack/day 0 + + + + + + + + Poor diet 0 0 + + + + + + + Abuse 0 0 0 + + + + + + Age >30 0 0 0 0 + + + + + Education <12 0 0 0 0 0 + + + + Unmarried 0 0 0 0 0 0 + + + Little Prenatal Care 0 0 0 0 0 0 0 + + Previously Affected Child 0 0 0 0 0 0 0 0 +

Symptomatology + - Imagining + _

Symptomatology Dimensional Criteria Categorical Cutoff . Categorical Criteria Diagnosis + - Imaging + imaging refinement to include minimum numbers of positive cases or positive criteria + _

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 gene; † gene without diagnosis. TP = true positives; TN = true negatives; FP = false positives; FN = false negatives

Symptomatology Imagining + + - _ Positive Findings Positive Imaging + - Imagining + Positive Findings Positive Imaging Negative Findings _ Negative Imaging

Cases of FASD 1% 99%

Possible Cases + - Cases 1% 3% Possible Cases + 3% 93% -

Focus of Clinicians Focus of Research

Transmission of Effects Familial Generational Genetic

FASD - Genetic Often has a pattern susceptibility Protective Casual chain

FASD - Familial Familial effects COA

FASD - Generational What is transmitted How is it transmitted

Generational Genetic Familial

Increased Probability of a Previous Child with Fetal Alcohol Syndrome Total number of live births prior to birth of FAS child Number of children with FAS in prior births Estimated incidence of FAS per 1,000 live births Incidence of FAS in previous births per 1,000 live births Risk increased by 135 23 .97 170.4 172x Source: E.L> Abel, Fetal Alcohol Syndrome in Families, Neurotoxicity and Teratology (1988), 10, pp.1-2. Copyright 1988 by Elsevier Science, Adapted with permission of the publisher.

Increased Risk of Having a Second Child with Fetal Alcohol Syndrome Total number of live births after birth of FAS child Number of children with FAS in subsequent births Estimated incidence of FAS per 1,000 live births Incidence of FAS in subsequent births per 1,000 live births Risk increased by 35 27 .97 771 795x Source: E.L> Abel, Fetal Alcohol Syndrome in Families, Neurotoxicity and Teratology (1988), 10, pp.1-2. Copyright 1988 by Elsevier Science, Adapted with permission of the publisher.

Mortality

Mortality in a Ten-Year Follow-Up of FAS Children. 18% cases Mortality in a Ten-Year Follow-Up of FAS Children 18% cases 27% of the Mothers (Streissguth, 1985)

Diagnosis of People with Adverse Outcome from Prenatal Alcohol Exposure Specific Pattern of Malformations. Confirmed History of Maternal Alcohol Use-Abuse. Specific Pattern of Neurocognitive Deficits.

Growth 100% Diagnosed Diagnosis Cases < 10 Weight 100% Diagnosed Height

Diagnosis of Adverse Outcomes from Prenatal Alcohol Exposure Pattern Malformations All are common Many appear together Maternal Alcohol Use-Abuse Only 10-15% moms accompany children Moms rarely interviewed Cousin, aunt, friend, neighbor, police Neurocognitive Deficits I Q - normed V-P split Neuropsychological Findings Cutoff – Abnormal test only % present in population with FAS without FAS

Syndromal Variation Highly Variable Phenotype # Severe Classic Phenotype Variation

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

Highly Variable Phenotype Syndromal Variation Highly Variable Phenotype CL & P Mortality ADHD Learning Disabilities Pregnancy Losses Hearing Impairment Number of Cases Mental Disorders Fertility Visual Impairment Birth Defects Severe Cognitive Deficits Infectious Illness Increased Severity Classic Phenotype Variation

“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

We have exact standards for trees. We do not want to label or stigmatize.

Inaccurate Diagnosis: Stigmatization of Mother Labeling of Child Diagnostic Imprecision Parents Schools Doctors Epidemiologist Apathy

Consequences of Misdiagnosis Public Health Inaccurate Prevalence Outcome Causal Factors Cost Estimates Service Systems

Consequences of Misdiagnosis Mothers Recurrence Health Death Guilt Search for what’s wrong

Consequences of Misdiagnosis Child Misunderstood Behavior Inappropriate Treatment Secondary Disabilities Jail Substance Abuse Multiple Foster Homes Unnecessary testing

Consequences of Misdiagnosis Society Cost Low Priority for funding Recurrence Loss of Potential Infant-child Mortality Rate Increased Severity

Consequences of Misdiagnosis Mothers Recurrence Health Death Guilt Search for what’s wrong Public Health Inaccurate Prevalence Outcome Causal Factors Cost Estimates Service Systems Child Misunderstood Behavior Inappropriate Treatment Secondary Disabilities Jail Substance Abuse Multiple Foster Homes Unnecessary testing Society Cost Low Priority for funding Recurrence Loss of Potential Infant-child Mortality Rate Increased Severity

Velocardiofacial Syndrome Protective Effect Williams Syndrome Dubowitz Syndrome Velocardiofacial Syndrome Downs Syndrome Cerebral Palsy Spina Bifida

Current Imprecision (Top 10) Very few centers able to diagnose To complicated for most doctors Most moms missed Most children mislabeled Poor prevalence estimates Inadequate funding Low public health priority Generational recurrence High familial recurrence rate Inappropriate treatment – could but won’t

Co-Morbidity Weighting Multiple Events Impact assessment

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

Impairments in: Memory Attention Adaptive behavior Use of social rules Sleep Behavior regulation