Enviromics

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Enviromics

• By
• Larry Burd, Ph.D.
• Professor, Department of Pediatrics
• Director, North Dakota Fetal Alcohol Syndrome
  Center
• University of North Dakota, School of Medicine
  and Health Sciences
• Grand Forks, ND
• E-maillaburd_at_medicine.nodak.edu

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Enviromics

• The study of environmental effects

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Concepts
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Phenome Phenomics Phenotype
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Genomics DNA RNA Protein Effect Size
Enviromics Exposure Dose Action Effect Size
Phenotype
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Enviromics Genomics

• Exposure
• Dose
• Effect
• Effect Size

• DNA
• RNA
• Protein
• Metabolites

Phenotype
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Enviromic Components

• Models
• Exposures
• Prevalence
• Effect
• Magnitude
• Timing
• Interactions
• Confounders
• Phenotype Variance

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• Variance in Phenotype (Vp)
• Variance in Genetic Factors (Vg)
• Variance in Environmental Factors (Ve)

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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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Enviromics Casual Effect
Modifiers No Known
Effect Confounders Interactions
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Dosiometry
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• Fetal
• Maternal
• Organ System
• Function/Behavior

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Exposure
0 High
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EXPOSURE Units/Dose

• Cigarettes
• 1. per day
• 2. Total Exposure
• 3. Cotine level per trimester of pregnancy
• Head Injury
• 1. of events
• 2. Time in coma
• Genetics
• Duplication
• Trisomy 21 Syndromal Variablity
• Expansion Repeats
• Trinucleotide repeats
• Fragile X Mental Retardation
• IQ
• Mytonic Dystrophy Age Onset
• Rate Progression
• Imprinting
• Gene Silencing RNA
• Phenotype Expression

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Smoking
Chart Data

• Weekends Packs OCC

X
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Chart Data
Smoking

• 1 pack Occ
• 7-15 light heavy
• Has cut down

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Alcohol
Chart Data

• X - Y - -

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Alcohol
Chart Data

• 2 day 3 4 weekend
• Quit cut down
• Needs treatment?
• 2 DUIs

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Units of Exposure
0 High
Cigarettes day week pregnancy cotine levels
Drinks day week binges (4/5) pregnancy BAL
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Threshold
Severe
Outcomes
Protective
0 Exposure Dose High
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Linear non-Threshold
Severe
Outcomes
0 Exposure Dose High
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Hormetic
Severe
Outcomes
0 Exposure Dose High
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Each Exposure Should be Considered an Episode

• Temporal parameters
• Dose

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Profile of Exposure Episodes
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Physiologically based pharmacokinetics model
(PBPK)
Genes condition 2, 3, or 4 hit model
Genetic predisposition
Developmental stage
Exposure
Interaction
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Elimination Kinetics

• Absorption
• Distribution
• Metabolism
• Excretion

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Exposure AssessmentandPhenotype Detectability
areInterdependent
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Phenotype
Severe
Absent
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Phenotype Detectability
Severe
Absent
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Phenotype Detectability
Severe
Severe
Phenotype
Detectability
Absent
Absent
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Coherence Threshold
Accuracy
Phenotype

• Sensitivity
• Specificity
• Positive predictive
• value
• Negative predictive
• value
• Accuracy

Dose
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Exposure and Phenotype are linked.Dose
Detectability
0 High
Absent High
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Cost of Exposure
Excess Costs
Phenotype Prevalence or Severity 0
Cost Savings
Exposure/Dose
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Cost of Exposure
Excess Costs

• Unitize
• Exposure
• Prevalence
• Severity
• Costs
• Cost per
• outcome
• or
• Costs per unit
• of exposure

Phenotype Prevalence 0
Cost Savings
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Phenotype Detectability

• Detection
• Classification

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Detection Sensitivity
Syndrome
High
Low
Severe Syndrome Mild
Increased prevalence of signs
Testing Control Group
Observation Testing
Syndrome and comorbidity
Normal Tests
Mortality
Observation
Mortality
Typical Syndrome
NOAEL None

TOEL Typical
LD 50 Lethal
LOEL Low
Exposure (Dose)
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Disease Status
-
DiagnosticStatus
Diagnosis with no exposure exposure without
diagnosis.
TP true positives TN true negatives
FP false positives FN false negatives
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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

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Susceptible Exposed Unexposed
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Adverse Outcomes Due to Prenatal Alcohol Exposure

• Did mom drink?
• Did she drink enough?
• Abnormal signs or disorders?
• Yes or No
• Was Alcohol a contributor to outcome?

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SCREENING FOR ALCOHOL ABUSE TWEAK Test (Russell
1984)  TOLERANCE How many drinks can you hold?
If more than 5 drinks 2 points  WORRY Have
close friends or relatives worried or complained
about Your drinking in the past year? Yes 2
points EYE-OPENER Do you sometimes take a drink
in the morning when you first get up? Yes 1
point AMNESIA Has a friend or family member ever
told you about things you said or did while you
were drinking that you could not remember? Yes
1 point    K/CUT DOWN Do you sometimes feel the
need to cut down on your drinking? Yes 1
point    A score of 2 or above places the woman
in a risk category and requires further
assessment.
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Estimating Dosage

• Fetal
• Drinks per drinking day
• Days per week
• Binge days
• 1st Trimester
• Last Trimester
• At labor and delivery
• Cumulative dose

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Estimating Dosage

• Maternal Cumulative (Lifetime)
• Drinks per drinking day
• 1st drink
• 1st drunk
• 1st treatment
• 1st pregnancy
• Each treatment
• Each pregnancy

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Exposure
Critical Susceptibility Components
Dose Duration Timing

• Alcohol
• Binges
• Total Dose
• Days Exposed

Genetics Age Education Diet Smoking Birth
Order Previously Affected Child Paternal effects
Necessary but not sufficient
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Cumulative Dose to Event
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• Assessment of Exposure During Pregnancy
• On average how many days per week did you drink
  during pregnancy? _____(a)
• What is the most you had to drink on any one day
  during pregnancy? _____
• On an average drinking day during pregnancy how
  many drinks did you have? _____(b)
• Exposure Parameters (Cumulative exposure during
  pregnancy)
• Pregnancy Drinking Days ( a x
  40 ) _____(c)
• Estimate of number of drinking days during
  pregnancy.
• Percent of Days Exposed During Pregnancy (
  c 280 )
• Estimate of days exposed during pregnancy.
  _____
• Number of Drinks During Pregnancy ( a
  x b x 40 )
• Estimate of number of drinks during pregnancy.
  _____(d)
• Ounces of absolute alcohol ( d 2 )
  _______
• Estimate of exposure to absolute alcohol during
  pregnancy.

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FASDPhenotypes
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Synergistic Effects
Exposure Adverse outcome Expression
Threshold Phenotype Severity Mortality LD - 50

• Concept

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Synergistic Effects
Application
Exposure Heart Defect Mortality
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ModelingExposureOutcomes
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Outcomes
High
Exposoure
Low
ARND FAS Fetal Stillbirth Infant
Death Mortality
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Outcomes
High
Exposure
Low
Fetal Stillbirth Infant FAS ARND Death
Mortality
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Outcomes
High
Exposure
Low
Fetal Stillbirth Infant FAS ARND Death
Mortality
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Concluding ThoughtsPhenotype and Exposure are
Linked

• Exposure dose
• Exposure profile
• Phenotype detectability
• Dose phenotype
• Refinement of measures