Enviromics By Larry Burd Ph D Professor Department
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-mail: laburd@medicine. nodak. edu
Enviromics: The study of environmental effects
Concepts Phenomics Enviromics Genomics
Envirome Enviromics Exposures Phenome n = thousands Genome Genomics DNA n = thousands Transcriptomi cs Transcriptomics Proteome Proteomics RNA all Phenomics n = thousands Protein all n = thousands Metabolome Metabolomics Biochemicals n = hundreds Phenotype
Enviromics Genomics Exposure DNA Dose RNA Action Protein Effect Size Phenotype
Enviromics Genomics Exposure DNA Dose RNA Effect Protein Effect Size Metabolites Phenotype
Enviromic Components n n n Models Exposures Prevalence n n n Effect Magnitude Timing Interactions Confounders Phenotype Variance
n n n Variance in Phenotype (Vp) Variance in Genetic Factors (Vg) Variance in Environmental Factors (Ve)
Variance in Phenotype Vp = Vg + Ve n Modeling Variance Estimates Vp = Vg + Ve n Ve = Vp – Vg n Vg = Vp - Ve n
Enviromics Casual Effect Modifiers Confounders No Known Effect Interactions
Dosiometry
Fetal n Maternal n Organ System n Function/Behavior n
Exposure 0 High
Cigarettes EXPOSURE: Units/Dose 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 Expansion – Repeats Trinucleotide repeats Fragile X Mytonic Dystrophy Imprinting Gene Silencing = Syndromal Variablity = Mental Retardation IQ = Age Onset Rate Progression = RNA Phenotype Expression
Chart Data Smoking: + Weekends + X Packs OCC
Chart Data Smoking: 10 1 pack Occ 7 -15 light heavy Has cut down
Chart Data Alcohol: X + + - Y - -
Chart Data Alcohol 2 day 3– 4 Quit cut down Needs treatment? 2 DUI’s * weekend
Units of Exposure 0 High Drinks Cigarettes day week binges (4/5) pregnancy BAL day week pregnancy cotine levels
Threshold Outcomes Severe Protective 0 Exposure Dose High
Linear non-Threshold Outcomes Severe 0 Exposure Dose High
Hormetic Outcomes Severe 0 Exposure Dose High
Each Exposure Should be Considered an Episode Temporal parameters n Dose n
Profile of Exposure Episodes
Physiologically based pharmacokinetics model (PBPK) Genes “+” condition 2, 3, or 4 hit model Genetic predisposition Exposure Developmental stage Interaction
Elimination Kinetics Absorption n Distribution n Metabolism n Excretion n
Exposure Assessment and Phenotype Detectability are Interdependent
Phenotype Severe Absent
Phenotype Detectability Severe Absent
Phenotype Detectability Severe Phenotype Detectability Absent
Coherence Threshold Accuracy Phenotype Dose • Sensitivity • Specificity • Positive predictive value • Negative predictive value • Accuracy
Exposure and Phenotype are linked. Dose Detectability 0 Absent High
Cost of Exposure Excess Costs Phenotype Prevalence or Severity 0 Cost Savings Exposure/Dose
Cost of Exposure Excess Costs Phenotype Prevalence 0 Cost Savings Unitize: • Exposure • Prevalence • Severity • Costs = Cost per outcome or • Costs = per unit of exposure
Phenotype Detectability Detection n Classification n
Detection Sensitivity Syndrome High Low Severe Mortality Increased Testing & prevalence Control of. Group signs Normal Syndrome Tests Observation Syndrome Observation Typical and & Testing Syndrome comorbidity Mild NOAEL LOEL TOEL LD – 50 None Low Typical Lethal Exposure (Dose)
Disease Status + + Diagnostic Status - - True positives = False positives = TP+TN+phenocopies* ___ FP+FN+phenocopies† ___ 100% % 100 False Negatives = True negatives = FN+TN+phenocopies* ___ FP+TP+phenocopies† ___ 100% % 100 *Diagnosis with no exposure; † exposure without diagnosis. TP = true positives; TN = true negatives; FP = false positives; FN = false negatives
Exposure vs. Significant Exposure n NOEL n n LOAEL n n Lowest Observable Adverse Effect Level TAEL n n No Observable Effect Level Typical Adverse Effect Level: 50% with adverse outcome at exposure level LD – 50 n Lethal Dose for 50% exposed
Susceptible Exposed Unexposed
Adverse Outcomes Due to Prenatal Alcohol Exposure n Did mom drink? n Did she drink enough? n Abnormal signs or disorders? Yes n or No Was Alcohol a contributor to outcome?
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.
Estimating Dosage n Fetal Drinks per drinking day n Days per week n Binge days n 1 st Trimester n Last Trimester n At labor and delivery n Cumulative dose n
Estimating Dosage n Maternal Cumulative (Lifetime) Drinks per drinking day n 1 st drink n 1 st drunk n 1 st treatment n 1 st pregnancy n Each treatment n Each pregnancy n
Exposure Critical Dose Susceptibility Duration Components Timing n Alcohol n t en Binges i c i ff u ts n Total Dose n Days Exposed s ry a s N e c e o n t u b Genetics Age Education Diet Smoking Birth Order Previously Affected Child Paternal effects
Cumulative Dose to Event
Assessment of Exposure During Pregnancy n. On average how many days per week did you drink during pregnancy? _____(a) n. What is the most you had to drink on any one day during pregnancy? _____ n. On an average drinking day during pregnancy how many drinks did you have? _____(b) n Exposure Parameters (Cumulative exposure during pregnancy) §Pregnancy Drinking Days = ( a x 40 ) = §Estimate of number of drinking days during pregnancy. _____(c) §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. _______
FASD Phenotypes
Synergistic Effects Concept: Exposure Adverse outcome Expression Threshold Phenotype Severity Mortality LD - 50
Synergistic Effects Application: Exposure Heart Defect Mortality
Modeling Exposure Outcomes
Outcomes Exposoure High Low ARND FAS Fetal Stillbirth Infant Death Mortality
Outcomes Exposure High Low Fetal Stillbirth Infant FAS Death Mortality ARND
Outcomes Exposure High Low Fetal Stillbirth Infant FAS Death Mortality ARND
Concluding Thoughts Phenotype and Exposure are Linked Exposure dose n Exposure profile n Phenotype detectability n Dose – phenotype n Refinement of measures n
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