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.