MAL-ED Metabolic: A Follow-Up of Chronic Disease at Puberty

Study Overview
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Brief Summary
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The concept that the roots of cardiometabolic disease start in early life was established by Dr. David Barker, who documented relationships between low birthweight (as a marker for challenges during gestation) and later cardiovascular disease (CVD). Later work has suggested that post-natal challenges (similar to prenatal ones) may also exhibit links to later cardiometabolic disease, with the strongest links appearing to be between low weight in early childhood and later hypertension and high waist circumference (WC). However, assessments for the relationship between early childhood challenges and insulin resistance and glucose regulation have been lacking and long-term cohort studies are few. In this project, we aim to assess children initially followed as part of The Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health (MAL-ED) study, where they received frequent measures of anthropometry and laboratory assessments for intestinal pathogens. These children are now of peri-pubertal age--a time period associated with metabolic shifts. We will assess for glucose dysregulation and findings associated with the metabolic syndrome, and we will analyze potential associations between current chronic disease risk findings with early life poor growth and intestinal pathogen carriage rate. As such, we hope to uncover potential targets in early life health to reduce later chronic disease risk.

Detailed Description
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The relationship between prenatal challenges and later risk for chronic disease has been well established. Our group previously assessed the hypothesis that post-natal challenges (similar to prenatal ones) would exhibit links to later cardiometabolic disease. This was performed using retrospective data from a long-term cohort of children in Guatemala, demonstrating novel findings that higher degrees of diarrhea burden in the first 6 months of life (as a marker of nutritional and/or inflammatory stressors) were associated with a greater risk of metabolic syndrome as adults The causes of these findings are not known, though postulated mechanisms include epigenetic reprograming of metabolic rate, hormonal regulation and vascular tone. Unfortunately, long-term cohort studies are few, limiting opportunities to evaluate these links prospectively. The Haydom Global Health Research Center in north central Tanzania represents an important rural setting for performing high-quality medical research in sub-Saharan Africa (5). The region around Haydom has a high degree of stunting and enteric pathogen carriage among a cohort of children followed in the area from 2009-2013 as part of the multi-country study The Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health (MAL-ED). These children followed in Haydom during MAL-ED had monthly anthropometry and stool pathogen analysis, as well as extensive demographic data. This provides an opportunity to follow up on these children to assess for potential links between early life challenges (both enteric disease, infections and nutritional deficiencies) and later chronic disease risk, including lipid abnormalities, glucose intolerance and blood pressure elevations. The current proposal is to follow up on these children at the age of typical entry into puberty, as this is a common shift in metabolism when many children begin to exhibit metabolic abnormalities. We will assess these children for multiple measures: Anthropometry (height, weight, BMI, waist circumference) Assessment of pubertal stage by exam or questionnaire Blood pressure Lipids (LDL, HDL, triglycerides) CRP Oral glucose tolerance test (OGTT) Fasting insulin Metabolic syndrome (MetS) severity score Blood saved for future epigenetic testing We will use linear and and logistic regression to determine associations between 1) mean number of monthly pathogens (individual pathogens and in aggregate) and 2) reported symptoms (fever, cough, diarrhea), with multiple MetS-related outcomes: BMI percentile, WC, fasting insulin, 2-hour glucose following OGTT, triglycerides, HDL cholesterol, normalized BP and a MetS diagnosis. The underlying hypothesis is that there will be consistent links between features of MetS (in particular blood pressure, waist circumference and insulin resistance) with 1) enteric pathogen burden (overall and for particularly virulent pathogens such as Enterotoxigenic E.coli) and 2) poor early life growth.

Official Title
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MAL-ED Metabolic: A Follow-Up of Chronic Disease at Puberty

Conditions
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Growth Failure, Intestinal Infection, Metabolic Syndrome, Glucose Intolerance

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participated in original MAL-ED cohort Exclusion Criteria: Did not participate in original MAL-ED cohort

Ages Eligible for Study
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Minimum Age: 9 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| MAL-ED cohort<br>Children initially followed from birth through 2 years old in the MAL-ED study (with some additional assessments in follow-up studies since then). | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Current Systolic BP--relationship to number of enteric pathogens by age 2 years | Regression analysis of current systolic BP z-score vs. number enteric pathogens by age 2 years (from MAL-ED) | Measured during current study (1 year +/- 3 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Current Systolic BP--relationship to BMI z-score at age 2 years | Regression analysis of current systolic BP z-score vs. BMI z-score at age 2 years (from MAL-ED), adjusted for current BMI z-score | Measured during current study (1 year +/- 3 months) | 
| Current Diastolic BP--relationship to number of enteric pathogens by age 2 years | Regression analysis of current diastolic BP z-score vs. number enteric pathogens by age 2 years (from MAL-ED) | Measured during current study (1 year +/- 3 months) | 
| Current Diastolic BP--relationship to BMI z-score at age 2 years | Regression analysis of current diastolic BP z-score vs. BMI z-score at age 2 years (from MAL-ED), adjusted for current BMI z-score | Measured during current study (1 year +/- 3 months) | 
| Current BMI z-score--relationship to number of enteric pathogens by age 2 years | Regression analysis of current BMI z-score vs. number enteric pathogens by age 2 years (from MAL-ED) | Measured during current study (1 year +/- 3 months) | 
| Current waist circumference--relationship to number of enteric pathogens by age 2 years | Regression analysis of current waist circumference vs. number enteric pathogens by age 2 years (from MAL-ED) | Measured during current study (1 year +/- 3 months) | 
| Metabolic syndrome (MetS) severity score--relationship to number of enteric pathogens by age 2 years | Regression analysis of current MetS severity z-score vs. number enteric pathogens by age 2 years (from MAL-ED) | Measured during current study (1 year +/- 3 months) | 
| Current metabolic syndrome (MetS) severity score--relationship to BMI z-score at age 2 years | Regression analysis of current MetS severity z-score vs. number enteric pathogens by age 2 years (from MAL-ED), adjusted by current waist circumference | Measured during current study (1 year +/- 3 months) | 
| Current glucose from oral glucose tolerance test (OGTT) at 2 hours--relationship to number of enteric pathogens by age 2 years | Regression analysis of current 2-hour OGTT glucose vs. number enteric pathogens by age 2 years (from MAL-ED) | Measured during current study (1 year +/- 3 months) | 
| Current glucose from oral glucose tolerance test (OGTT) at 2 hours--relationship to BMI z-score at age 2 years | Regression analysis of current 2-hour OGTT glucose vs. BMI z-score at age 2 years (from MAL-ED), adjusted by current BMI z-score | Measured during current study (1 year +/- 3 months) | 
| Current fasting triglycerides--relationship to number of enteric pathogens by age 2 years | Regression analysis of current ln(triglycerides) vs. number enteric pathogens by age 2 years (from MAL-ED) | Measured during current study (1 year +/- 3 months) | 
| Current fasting triglycerides--relationship to BMI z-score at age 2 years | Regression analysis of current ln(triglycerides) vs. BMI z-score at age 2 years (from MAL-ED), adjusted by current BMI z-score | Measured during current study (1 year +/- 3 months) | 
| Current HDL cholesterol--relationship to number of enteric pathogens by age 2 years | Regression analysis of current HDL cholesterol vs. number enteric pathogens by age 2 years (from MAL-ED) | Measured during current study (1 year +/- 3 months) | 
| Current HDL cholesterol--relationship to BMI z-score at age 2 years | Regression analysis of current HDL cholesterol vs. BMI z-score at age 2 years (from MAL-ED), adjusted by current BMI z-score | Measured during current study (1 year +/- 3 months) | 
| Current fasting glucose--relationship to number of enteric pathogens by age 2 years | Regression analysis of current fasting glucose vs. number enteric pathogens by age 2 years (from MAL-ED) | Measured during current study (1 year +/- 3 months) | 
| Current fasting glucose--relationship to BMI z-score at age 2 years | Regression analysis of current fasting glucose vs. BMI z-score at age 2 years (from MAL-ED), adjusted by current BMI z-score | Measured during current study (1 year +/- 3 months) |