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
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.
The causal pie in adult disease
Peri diseasefactors
Young adult factors
Childhood factors
Genetic factors
?
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
Diseases proposed to have fetal origins
” Heart attack” Stroke” Hypertension” Diabetes” Obesity, Syndrome X”” Breast cancer” Osteoporosis
But “HOW”?
Possible mechanisms
”Does size matter?” 2500 g BWg16 g heart” 3000 g g 22 g heart
” (37.5% more heart)
Fetal placental vasculature?
Placenta presents ~50% of fetal peripheral vascular resistance
Fetal origins and diabetes
The thrifty phenotype?
Why the placenta?
The engine of fetal growth
Variability sufficient to account for findings
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
The “predictor” variables
” Disk shape” Larger and smaller diameters” Distance from cord insertion to disk edge” Cord length” Disk thickness” Placental weight
The outcome
” Birthweight” Childhood growth trajectory” Childhood neurodevelopmental scores” Adult disease
Shape
Shape: Round v. “not round”
Malposit ion
Villous destruction
Chorionic “belly button”
Umbilical cord insertion
Destruction
“Trophotropism”
Umbilical cord length
Cord length and cord function
Long supply lines are a problem
3 disk dimensions
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
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
Regression analysis Plan
” Linear terms ” Higher order terms” Interactions ” Local solutions (MARS 2.0)
Direct effects on BWDirect effects on PW
Indirect effects on BWIndirect effects on PW
(+)
Shape
Cord-edge
Large
Small
Cord length
PW
(+)
(-)
(+) (+)
(+)
(-)
(+)
BW
(-)
(+)
(+)
(+)
(+)
(-)
(-)
(-)
(+)(+)
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.
And so to MARS 2.0
Local solutions and their physiologic interpretation
Placental weight and birthweight
BW
PW
BW
PW
Interpretations
” No evidence for placental “senescence”
” “Post-maturity syndrome”
” “Fetal intolerance to labor”
BW
PW
BW effects
PW effects
β=16.5
β=26.4
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.
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
BW effects
PW effectsPonderal index
Fetoplacentalweight ratio
Fetoplacental weight ratio
BW effects
PW effects Ponderal index
Disk area interacts with disk thickness
Disk thickness
<10th 10th-90th
>90th
<10th tiny ? balancednormal
10th -90th
Normal
>90th ? balanced normal
BIG
Chorionicplate area
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
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?
RF Results
Random Forests and BW
RF predictive success
RF misclassification
RF ROC integral 0.87
What are the discriminators?
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.
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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