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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
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Study of Outcomes
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Detection Classification
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Severity Comorbidity Age
Phenome Phenomics Severity Comorbidity Age vs. Criteria Phenotype
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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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Variance in Phenotype Vp = Vg + Ve
Modeling Variance Estimates Vp = Vg + Ve Ve = Vp – Vg Vg = Vp - Ve
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Manifestation of Phenotype
Exposure Pathophysiology Impairment Disability Death
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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
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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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Fetal Alcohol Syndrome Causal Chain Elements Effect Size
Alcohol >14 oz Smoking >1 pack/day Poor diet Abuse Age > Education < Unmarried Little Prenatal Care Previously Affected Child
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Symptomatology Imagining + _
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Symptomatology Dimensional Criteria Categorical Cutoff Categorical Criteria Diagnosis Imaging + imaging refinement to include minimum numbers of positive cases or positive criteria + _
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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 gene; † gene without diagnosis TP = true positives; TN = true negatives; FP = false positives; FN = false negatives
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Symptomatology Imagining + + - _ Positive Findings Positive Imaging
Imagining + Positive Findings Positive Imaging Negative Findings _ Negative Imaging
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Cases of FASD 1% 99%
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Possible Cases + - Cases 1% 3% Possible Cases + 3% 93% -
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Focus of Clinicians Focus of Research
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Transmission of Effects
Familial Generational Genetic
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FASD - Genetic Often has a pattern susceptibility Protective
Casual chain
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FASD - Familial Familial effects COA
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FASD - Generational What is transmitted How is it transmitted
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Generational Genetic Familial
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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.
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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.
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Mortality
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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)
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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.
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Growth 100% Diagnosed Diagnosis Cases < 10 Weight 100% Diagnosed
Height
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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
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Syndromal Variation Highly Variable Phenotype # Severe Classic
Phenotype Variation
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Syndromal Variation Highly Variable Phenotype # Severe
Currently Diagnosed Classic Phenotype Variation
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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
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“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
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We have exact standards for trees.
We do not want to label or stigmatize.
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Inaccurate Diagnosis: Stigmatization of Mother Labeling of Child
Diagnostic Imprecision Parents Schools Doctors Epidemiologist Apathy
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Consequences of Misdiagnosis
Public Health Inaccurate Prevalence Outcome Causal Factors Cost Estimates Service Systems
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Consequences of Misdiagnosis
Mothers Recurrence Health Death Guilt Search for what’s wrong
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Consequences of Misdiagnosis
Child Misunderstood Behavior Inappropriate Treatment Secondary Disabilities Jail Substance Abuse Multiple Foster Homes Unnecessary testing
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Consequences of Misdiagnosis
Society Cost Low Priority for funding Recurrence Loss of Potential Infant-child Mortality Rate Increased Severity
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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
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Velocardiofacial Syndrome
Protective Effect Williams Syndrome Dubowitz Syndrome Velocardiofacial Syndrome Downs Syndrome Cerebral Palsy Spina Bifida
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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
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Co-Morbidity Weighting Multiple Events Impact assessment
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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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Impairments in: Memory Attention Adaptive behavior Use of social rules Sleep Behavior regulation
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