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“Balance, Fit”, intrauterine life and
lifelong diseasePreliminary analyses in the National
Collaborative Perinatal Project
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Levels of intervention
◦ Tertiary: Aimed at reducing the chronic effects of established disease.
◦ Secondary: Aimed at curing disease.
◦ Primary: Preventing disease.
Public health and intervention
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(insert pie chart) which includes:
◦ Peri disease factors
◦ Young adult factors
◦ Childhood factors
◦ Genetic factors
The causal pie in adult disease
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Ecologic
◦ High cardiovascular death rates in 1950 correlated with high infant mortality in the early 1900’s.
In an area of high infant mortality, “survivors” were still comparatively stressed.
Retrospective cohorts
◦ Nurses Health study, etc.
◦ Common feature- BW used as a surrogate for adequacy of the intrauterine environment
Fetal origins of adult disease
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Heart attack
Stroke
Hypertension
Diabetes
Obesity, syndrome X
Breast cancer
Osteoporosis
Diseases with “fetal origins” (associated with BW)
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Does size matter?
◦ 2500 g BW 16g heart
◦ 3000 g 22 g heart
(37.5% more heart)
Possible mechanisms
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“Small is bad”?
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Small or “relatively small”?
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The thrifty phenotype?
Fetal origins and diabetes
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29621 singleton liveborn infants
Standard placental measures◦ Shape
◦ Larger and smaller diameters
◦ Thickness
◦ Distance from cord insertion to the nearest disk edge
◦ Umbilical cord length
◦ Placental weight
Outcome variable: BW
The data set
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Disk shape
Larger and smaller diameters
Distance from cord insertion to disk edge
Cord length
Disk thickness
Placental weight
The “predictor” variables
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Birth weight
BMI at ages 4 and 7 years
The outcome
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Umbilical cord length
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3 disk dimensions
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Normal- 500 g
Abnormal 1st-2nd trimester, 500 g
Abnormal from 1st-2nd trimester, 250 g
Abnormal 3rd trimester, 400 g
Time-stamping abnormal growth
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Linear terms
◦ Higher order terms
◦ Interactions
Local solutions (MARS 2.0)
Regression Analysis Plan
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Indirect/Direct effects on BW
Indirect/Direct effects on PW
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Direct and Indirect Effects
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Pick 10 different random seeds
Get at least 9 different patterns of significant higher order terms and/or interactions
Inspection of distributions suggests differences lie with outlier partitioning
“significant” terms generally negative, indicating floor/ceiling effects
Problems with standard regression
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And so to MARS 2.0
Intrauterine “Balance” and childhood outcomes
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Placental weight and birth weight
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No evidence for placental “senescence”
“Post maturity syndrome”
“Fetal intolerance to labor”
Interpretations
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Fetal-placental weight ratio◦ How many grams of baby supported by each gram of
placental
◦ ~7:1 at term
◦ Too low placental dysfunction
◦ Too high↓ placental reserves
Ponderal index◦ Fatness ratio (weight*100/length^3)
◦ Third trimester weight gain
New terms
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Fetoplacental weight ratio
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PW and BW Effects
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PW and BW Effects continued
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Does bad “intrauterine balance” affect childhood growth?
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Interpretability of LR
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Interpretation: the cord length-age 7 BMI association is independent of PW
Age 7 BMI and cord length
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Cord length BW Age 7 BMI
Cord length Age 7 BMI= only at extreme cord lengths
Age 7 BMI, cord length, adj for BW
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◦ N= 36
◦ N~ 1000
◦ N~ 25,000
FPR knots used to categorize data
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N=240
N~ 23,000
N~ 3,000
FPR knots used to categorize data
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Recode BW into groups
◦ <2500 g: “Intrauterine growth restriction” Suggests chronic intrauterine deprivation
◦ >4000 g: Macrosomia Diabetic type metabolic pathology
◦ “Normal”
Can placental growth classify pathologic fetal growth that continues into childhood?
TreeNet, RF and Age 4 and 7 BMI
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Set penalties for misclassification
Score data
Incorrectly scored children are either bigger or smaller than expected given their placental dimensions◦ They don’t “fit” their placentas
Does “lack of fit” mark children’s growth trajectory?
Score data
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Class N Cases N Mis-Classed
% Error Cost
0 2,023 175 8.65 175
1 17,946 17,946 100.00 179,460
2 1,093 61 5.58 61
TreeNet classification:Misclassification for Learn Data
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TN BWT grp- Predgrp= “Wrong”
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Observed Predicted
<2500 2500-4000 >4000
<2500 10.8 11.1 11.4
2500-4000 10.0 11.4 12.0
>4000 10.9 11.4 11.8
Do “kids who don’t fit” differ from those who do? (Age 4 BMI)
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TN and RF scoring
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The placenta’s purpose is to “make a baby”
Values of placental dimensions where the placenta is bigger but the baby is not “unbalanced”
“Unbalanced” babies may be physiologically vulnerable and may have different childhood growth trajectories
Intrauterine “Balance”
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Your placenta provides all oxygen and nutrients and genetics aside is the principal determiner of fetal growth
If you are bigger or smaller than your placenta predicts, you don’t “fit”
Children who don’t “fit” may be physiologically vulnerable and have different childhood development trajectories
Intrauterine “fit”
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MARS and RandomForest allow complementary and unique insights into how placental growth is translated into fetal growth
Placental measures can be used to characterize the fetal environment, with physiologic and time-order inferences that may be important to “fetal origins” research
Summary