HBGDki Prioritized Questions

5 Key Questions
  1. To what extent is growth faltering explained by pre- vs postnatal insults?
  2. What kind of recovery can we expect in infants born small for gestational age (SGA)?
  3. Can we quantitatively characterize the relation and interaction between preterm birth, physical growth, and brain development?
  4. Are there disproportionately large contributions to growth faltering from specific pathways, and can we rank-order risk factors?
  5. Are there specific pathways directly impacting linear growth faltering that coincide with increased risk of noncommunicable diseases such as cardiovascular disease, obesity, and diabetes?

Prioritized questions

A list of HBGDKI's prioritized questions and which of the 5 questions they fall under.
HBGD WORKING GROUP QUESTION PRIORITY
A Are there genetic variants that contribute to birth weight/length/head circumference/body composition phenotype? What fraction of variability do these genetic variants explain? 11
A Characterize the (backward and forward) relationship between birth size across the first 1,000 days. 12
A Develop an allometric relationship between gestational age, post-conception age, chronological age, and developmental age through the first 1,000 days. 13
A Develop models to optimize (horizontal) timing and (vertical) ordering of combinations of interventions to have optimal durable efficacy? 14
A Develop predictive model(s) to identify the factors that do and do not contribute to the likelihood a woman will deliver preterm. 13
A Develop prenatal, postnatal, prenatal + postnatal growth predictive models to prospectively identify individuals at greatest risk of physical growth failure at 2yrs? What prenatal, postnatal, prenatal + postnatal risk factors drive the majority of the stunting/wasting burden? 14
A How accurately can we estimate gestational age from 20-40 weeks? Based on clinical variables alone, clinical variables + biomarker(s), ultrasound alone, ultrasound + clinical variables, ultrasound + clinical variables + biomarker(s)? 20
A How much do mother's and/or child's covariates explain observed between-subject variability? What proportion of growth failure is maternally driven (e.g., maternal height and/or maternal antenatal nutritional status)? Characterize the longitudinal relationship between maternal, and maternal + paternal height with child length from birth to 2yrs. 18
A How much of stunting present at birth and at 6 months of age is irreversible at age increments through to adulthood? 15
A How well? How early can we predict an individual child's growth trajectory through age 2? 16
A Is there a dose response for breastfeeding (duration and exclusive/non-exclusive on stunting at 2 yrs)? What does real world breast feeding data support as an optimal exclusive breast feeding duration? 13
A What are maternal (and fetal) predictors of good or poor response to antenatal steroids? How does response to antennal steroids relate to gestational age estimation uncertainty? 8
A What are the expected distributions of birth outcome measures (size (LAZ, HCZ, & WAZ) and gestational age)? 11
A What indicators are predictive of maternal infectious exposure or burden? How do iron-folate use and compliance impact infectious morbidities in either mother or baby? 9
A What is the effect size of genetics vs. environmental insults on birth outcomes, 6, 12 , 24 months? 13
A What is the expected distribution of LAZ and WAZ at 6 to 12 months of age? What is the unadjusted Z score distribution over 0-2 years as a function of PTB rate? 12
A What is the linkage between different early growth trajectories on child (stunting) on adult outcomes? 11
A What is the optimal interpregnancy interval and what is interpregnancy interval impact on pregnancy and newborn outcomes? 6
A What is the relationship between fetal linear growth velocity and risk of stunting over the first 2 years of life? 18
A What low birth weight/length cutoff (e.g., BW<2700g) is a good predictor of stunting at 2 (HAZ < -2) and what are the modifiers of this relationship? 14
A What maternal antenatal nutritional or other interventions will improve neurocognitive outcomes? 14
A What maternal antenatal nutritional or other interventions will reduce preterm birth risk? 15
A What maternal antenatal nutritional or other interventions will reduce stunting/wasting? How does maternal BMI impact maternal or neonatal outcomes? 18
A What minimum set of ultrasound variables (crown rump length (CRL), biparietal diameter (BPD), femur length (FL), head circumference (HC), occipitofrontal diameter (OFD), abdominal circumference (AC), and humerus length (HL), as well as estimated fetal weight (EFW))? minimum number of ultrasound visits? are required to remain within 10% of optimal preterm birth and birth outcome prediction sensitivity & specificity thresholds? 16
A What pregnancy/fetal/childhood nutritional or other interventions will reduce stunting/wasting by maintaining growth velocity? 19
A Which maternal/fetal covariates are most important in predicting birth outcomes (size (LAZ & WAZ), term, etc.)? How much variability do these covariates explain (at birth till 2 yrs)? What proportion of the variability in birth outcomes/linear size of children can we explain using maternal/all available covariates? 19
B Develop models to optimize (horizontal) timing and (vertical) ordering of combinations of interventions to have optimal durable efficacy? 16
B Does pre-term birth (*) SGA have additive or multiplicative consequence? What covariates explain observed variability? 15
B How do patterns of growth differ for early-, mid-, late-preterm & term SGA/AGA-births,... at 6 month intervals through 2-3 y of age? What are expected rates of stunting for early-, mid-, late-preterm SGA/AGA births? What are the factors that result in “recovery”? How do they differ by underlying risk, sex, etc.? 17
B What is the permanent deficit in height associated with early-, mid-, late-preterm & term SGA/AGA-births and stunting at birth? What fraction of observed variability is explained by available covariates? 12
B What is the risk relationship between early- (WHO-extremely preterm (<28 weeks)), mid- (WHO very preterm (28 to <32 weeks), late-preterm (WHO- moderate to late preterm (32 to <37 weeks) & term SGA/AGA-births and stunting/wasting during postnatal life? 15
B What is the time window and what are the factors that result in “recovery”? What are modifiers and how does the potential to recover differ by context? 18
B What maternal antenatal nutritional or other interventions will improve neurocognitive outcomes? 16
B What maternal antenatal nutritional or other interventions will reduce stunting/wasting for SGA infants? 17
C Correlate strongly with measures of physical size and growth? 19
C Develop models to optimize (horizontal) timing and (vertical) ordering of combinations of interventions to have optimal durable efficacy? 16
C How early in development can we detect impairments? When in the lifecycle are impairments reversible/irreversible? 20
C How much variability in childhood cognitive outcomes is explained by clinical/demographic covariates (e.g., maternal height, birth weight, etc.) 16
C Isolate predictive items in battery of (neuro)assessment tools? 20
C Predict later assessments at 3-6 years, 7-10 years, and adult outcomes (including school achievement, employment, SES)? 22
C Quantify the temporal relationship between stunting/wasted and impaired neurodevelopment from birth to 2yrs? 21
C To what extent is neurodevelopment impairment explained by preconception vs. prenatal vs. postnatal insults? 20
C What constitutes “normal/healthy” neurodevelopment (e.g., functional, structural, behavioral) in our prioritized LMIC settings? 17
C What infant and childhood biological (e.g., nutritional, WSH, infection control) and/or psychosocial (e.g., nurturing, stimulation, access to quality early education and childcare) interventions will improve neurocognitive outcomes? 22
C What maternal antenatal nutritional, mental health support, educational or other interventions will improve neurocognitive outcomes? 20
C What neurodevelopment assessments and/or emerging physiological tools produce results that: predict later neurodevelopment assessments?
C Which domains of cognitive function are differentially impacted by different conditions of preterm birth and fetal growth restriction or postnatal insults? 16
D Develop a model to enable plausible exploration of the interaction of nutrition quantity/quality, infection, inflammation, gut function (altered microbiome, altered barrier function), and immune system interact to contribute to stunting? What is the energy budget cost? 13
D How does the body composition of children in under-resourced environments (where they are born small and experience growth faltering) differ from healthy growing babies through the 2nd & 3rd trimester, at birth and in the first 2-3 years of life? What covariates explain observed variability? 12
D To what extent do microbiome, epithelium, submucosa insults impact nutrient absorption, host/microbiome metabolites, and linear growth? 14
D To what extent does enteropathogen burden vs. nutrition vs. environmental toxin vs. maternal factors (epigenetics, breast milk quality) contribute to growth stunting? 19
D To what extent is growth failure maternally driven (e.g. immature breast milk and its effect on the microbiome) vs. fetus/infant/child determined? 17
D To what extent is gut development (microbiome, epithelium, submucosa) impacted in preterm birth? 13
D What effect size can we expect if we provide RDA levels of protein for our priority outcomes (SGA/LBW, stunting) in the background of EED and/or infection? 16
D What is the (range of normal) body composition of healthy growing babies through the 2nd & 3rd trimester, at birth and in the first 2-3 years of life? What covariates explain observed variability? 12
D What microbiome, metabolome, and epigenomic factors are shared in metabolic syndrome and growth stunting (e.g. metabolic inflexibility, inflammation, TMAO pathways, rDNA methylation) 9
D What pathways mediate fetal/infant/childhood nutritional or other interventions by maintaining growth velocity? 13
E How does both maternal and child nutrition effect epigenetic changes in the genome, how do these changes contribute to altered growth, and to what extent are these changes mutable? 9
E What is the cumulative lifecycle-related cardiometabolic risk of childhood interventions (nutritional or others) at any age of follow-up? 14
E What is the cumulative lifecycle-related cardiometabolic risk of pre/peri & pregnancy targeted interventions (that may or may not have resulted in improvements in birth outcomes) in the offspring at any age of follow-up? 13
E What is the effect size of genetics vs. environmental insults on birth outcomes, 6, 12 , 24 months? 11