salford methods and the “fetal origins” hypothesisdocs.salford-systems.com/salafia.pdf · fetal...
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Salford methods and the “Fetal origins”
hypothesis
Preliminary analyses in the National Collaborative Perinatal
Project
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Public health and intervention
” Levels of intervention” Tertiary: Aimed at reducing the chronic effects of
established disease.” Secondary: Aimed at curing disease.” Primary: Preventing disease.
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The causal pie in adult disease
Peri diseasefactors
Young adult factors
Childhood factors
Genetic factors
?
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Fetal origins of adult disease
” 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
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Diseases proposed to have fetal origins
” Heart attack” Stroke” Hypertension” Diabetes” Obesity, Syndrome X”” Breast cancer” Osteoporosis
But “HOW”?
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Possible mechanisms
”Does size matter?” 2500 g BWg16 g heart” 3000 g g 22 g heart
” (37.5% more heart)
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Fetal placental vasculature?
Placenta presents ~50% of fetal peripheral vascular resistance
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Fetal origins and diabetes
The thrifty phenotype?
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Why the placenta?
The engine of fetal growth
Variability sufficient to account for findings
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The data set
” 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
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The “predictor” variables
” Disk shape” Larger and smaller diameters” Distance from cord insertion to disk edge” Cord length” Disk thickness” Placental weight
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The outcome
” Birthweight” Childhood growth trajectory” Childhood neurodevelopmental scores” Adult disease
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Shape
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Shape: Round v. “not round”
Malposit ion
Villous destruction
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Chorionic “belly button”
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Umbilical cord insertion
Destruction
“Trophotropism”
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Umbilical cord length
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Cord length and cord function
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Long supply lines are a problem
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3 disk dimensions
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Critical Periods in Early Placental Critical Periods in Early Placental DevelopmentDevelopment
E
1str 2ndr 3rdr
Villous atrophy
Embryo folding
Nonuniform disk expansion
Asymmetric disk growth
Villous arborization
““
Chorionic angiogenesis
Chorionic vasculogenesis
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Time-stamping abnormal growth
Normal- 500 g Abnormal 1st-2nd trimester,500 g
Abnormal 3rd trimester,400 g Abnormal from 1st-2nd trimester,
250 g
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Regression analysis Plan
” Linear terms ” Higher order terms” Interactions ” Local solutions (MARS 2.0)
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Direct effects on BWDirect effects on PW
Indirect effects on BWIndirect effects on PW
(+)
Shape
Cord-edge
Large
Small
Cord length
PW
(+)
(-)
(+) (+)
(+)
(-)
(+)
BW
(-)
(+)
(+)
(+)
(+)
(-)
(-)
(-)
(+)(+)
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Problems with standard regression
” 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.
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And so to MARS 2.0
Local solutions and their physiologic interpretation
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Placental weight and birthweight
BW
PW
BW
PW
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Interpretations
” No evidence for placental “senescence”
” “Post-maturity syndrome”
” “Fetal intolerance to labor”
BW
PW
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BW effects
PW effects
β=16.5
β=26.4
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Proposed interpretation
” After ~25 cm width, larger diameters do not contribute to increasing BW or PW.” Is there an optimum girth? Are “supply lines” over
burdened?
” There is a persistent benefit of uniform expansion of the disk.” Uniform growth indicates a uniformly receptive
intrauterine environment.
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New terms
” Fetal-placental weight ratio” How many grams of baby supported by each
gram of placenta” ~7:1 at term
” Too lowgplacental dysfunction” Too highgkplacental reserves
” Ponderal index” Fatness ratio (weight*100/length3)” Third trimester weight gain
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BW effects
PW effectsPonderal index
Fetoplacentalweight ratio
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Fetoplacental weight ratio
BW effects
PW effects Ponderal index
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Disk area interacts with disk thickness
Disk thickness
<10th 10th-90th
>90th
<10th tiny ? balancednormal
10th -90th
Normal
>90th ? balanced normal
BIG
Chorionicplate area
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FPR PIDisk thicknessDisk thickness
8.5 8.2 7.4
7.9 7.5 6.9
7.3 6.8 6.1
2.42 2.45 2.45
2.59 2.56 2.58
2.64 2.67 2.66
CPareaCP
area
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Random Forests and BW
” 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?
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RF Results
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Random Forests and BW
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RF predictive success
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RF misclassification
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RF ROC integral 0.87
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What are the discriminators?
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Summary
” MARS and Random Forest 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.
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Summary” MARS and Random Forest 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.