Evaluating the Alimentary and Respiratory Tracts in Health and Disease (EARTH) Research Program.

Study Overview
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Brief Summary
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The investigators have established the Evaluating the Alimentary and Respiratory Tracts in Health and disease (EARTH) research program. It provides a structured approach to analysing gastrointestinal and respiratory microbiomes, along with diet and symptomatology, in children with a gastrointestinal and/or respiratory condition with recognised long-term morbidity (e.g. cystic fibrosis, obstructive sleep apnoea, or Hirschsprung's disease). The EARTH program consists of a series of prospective, longitudinal, controlled, observational studies, with each individual study comparing children with a chronic gastrointestinal and/or respiratory condition to healthy controls (HC). It will be conducted in an Australian tertiary paediatric hospital (although the methodology is applicable to other settings). Children with a chronic gastrointestinal and/or respiratory condition will be compared to age and gender matched HC across a 12-month period. The following will be collected at baseline, 6 and 12 months: (i) a stool sample, (ii) an oropharyngeal swab or sputum sample, (iii) a semi-quantitative food frequency questionnaire, (iv) details of disease symptomatology, (v) health-related quality of life, and (vi) psychosocial factors. Data on the intestinal and respiratory microbiomes and diet will be compared between children with a condition and HC. Correlations between dietary intake (energy, macro- and micro-nutrients), intestinal and respiratory microbiomes within each group will be explored. Data on disease symptomatology, quality of life and psychosocial factors will also be compared between children with a condition and HC. The investigators hypothesise that: (i) Children with chronic gastrointestinal and/or respiratory conditions will have altered intestinal and respiratory microbiomes compared to healthy children, and (ii) Diet plays a key role in influencing the intestinal and respiratory microbiomes and this may impact on clinical outcomes, biomarkers of disease, and health-related quality of life.

Detailed Description
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The objective of this research program is to evaluate and compare children with a chronic gastrointestinal and/or respiratory condition and age and gender matched HC. The primary objectives include analysing the intestinal and respiratory microbiomes (using an integrated omics approach) and dietary intake using validated, food frequency quetsionnaires. The secondary objectives include evaluating: Known inflammatory biomarkers. Symptomatology and health-related quality of life (HRQOL) using validated measures. Phenotypic and clinical information. Sociodemographic factors Additional secondary objectives include correlating within children with the same condition: (i) dietary intake with the intestinal microbiome; (ii) dietary intake with the respiratory microbiome; and (iii) the intestinal and respiratory microbiomes. The investigators hypothesise that: (i) Children with chronic gastrointestinal and/or respiratory conditions will have altered intestinal and respiratory microbiomes compared to healthy children, and (ii) Diet plays a key role in influencing the intestinal and respiratory microbiomes and this may impact on clinical outcomes, biomarkers of disease, and health-related quality of life. To our knowledge, this program will enable the first series of studies comparing the intestinal and respiratory microbiomes and diet in children with chronic gastrointestinal and/or respiratory conditions. Initial results will be hypothesis-generating and used to direct future studies tailored to a specific focus or line of inquiry. Additionally, studies from this research program have potential for direct translation into clinical care as diet is a highly modifiable factor. Study design. The EARTH program provides a framework for a series of prospective, longitudinal, controlled, observational studies, with each individual study comparing children with a chronic gastrointestinal and/or respiratory condition to HC. A single healthy control group will be used for comparison against all conditions. The standardised methodological approach will also allow for comparisons between different health conditions. Procedures. Each participant will be assessed on three occasions over a 12-month period; at study entry, 6- and 12-month follow-up. At each time-point, the following will be collected: A stool sample; An oropharyngeal swab or sputum sample (a sputum sample will be obtained in children able to expectorate and an oropharyngeal swab will be collected in children unable to expectorate); Dietary intake measured using the Australian Child and Adolescent Eating Survey (ACAES) (2 to 18 years) or 24-hour food recall (0 up to 2 years); A secure, password-protected online survey comprising: i. PedsQL Infant Scales (0-2yr) & Gastrointestinal Symptoms Module (2-18yr),41-43 tailored to age; ii. Rome IV Questionnaire (0 to 18 years); iii. Spence Children's Anxiety Scale (3 to 18 years); iv. Short Mood and Feelings Questionnaires (6 to 18 years); v. Clinical and biochemical results obtained through routine care and hospitalisations (if available); vi. Sociodemographic factors (baseline survey only); Anthropometrics: height, weight and BMI z-scores.

Official Title
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Evaluating the Alimentary and Respiratory Tracts in Health and Disease (EARTH) Research Program.

Conditions
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Cystic Fibrosis, Hirschprung's Disease, Obstructive Sleep Apnea, Healthy

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Are aged between 0 and 18 years; Have been diagnosed with a chronic gastrointestinal and/or respiratory condition defined by consensus diagnostic criteria; or Are free of any chronic health condition (healthy control group); and Have a parent(s)/carer(s) who provides informed consent, or are at least 16 years old and provide informed consent. Exclusion Criteria: Children who have an unrelated coexisting chronic medical illness(es) associated with alterations in dietary intake or suspected alterations in the intestinal and/or respiratory microbiomes; Inability to comply with study requirements; Parent(s)/guardian(s) are unable to speak English or do not have a reading level age of at least 12 years.

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cystic fibrosis<br>Children diagnosed with cystic fibrosis. Children aged between 0 and 18 years. | |
| Hirschsprung's disease<br>Children diagnosed with Hirschsprung's disease. Children aged between 0 and 18 years. | |
| Obstructive sleep apnoea<br>Children diagnosed with obstructive sleep apnoea. Children aged between 0 and 18 years. | |
| Healthy controls<br>Children free of any chronic health condition. Children aged between 0 and 18 years. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1A.i.0 Intestinal Microbiome (Bacteria) - Richness | Measurement of alpha diversity (assessed using 16S rRNA or metagenomic gene sequencing). | Baseline | 
| 1A.i.6 Intestinal Microbiome (Bacteria) - Richness | Measurement of alpha diversity (assessed using 16S rRNA or metagenomic gene sequencing). | Change from baseline at 6 months | 
| 1A.i.12 Intestinal Microbiome (Bacteria) - Richness | Measurement of alpha diversity (assessed using 16S rRNA or metagenomic gene sequencing). | Change from baseline at 12 months | 
| 1A.ii.0 Intestinal Microbiome (Bacteria) - Shannon index | Measurement of alpha diversity (assessed using 16S rRNA or metagenomic gene sequencing). | Baseline | 
| 1A.ii.6 Intestinal Microbiome (Bacteria) - Shannon index | Measurement of alpha diversity (assessed using 16S rRNA or metagenomic gene sequencing). | Change from baseline at 6 months | 
| 1A.ii.12 Intestinal Microbiome (Bacteria) - Shannon index | Measurement of alpha diversity (assessed using 16S rRNA or metagenomic gene sequencing). | Change from baseline at 12 months | 
| 1A.iii.0 Intestinal Microbiome (Bacteria) - UNIFRAC distances | Measurement of beta diversity (assessed using 16S rRNA or metagenomic gene sequencing). | Baseline | 
| 1A.iii.6 Intestinal Microbiome (Bacteria) - UNIFRAC distances | Measurement of beta diversity (assessed using 16S rRNA or metagenomic gene sequencing). | 6 months | 
| 1A.iii.12 Intestinal Microbiome (Bacteria) - UNIFRAC distances | Measurement of beta diversity (assessed using 16S rRNA or metagenomic gene sequencing). | 12 months | 
| 1A.iv.0 Intestinal Microbiome (Bacteria) - relative abundances of bacteria | ANCOM analysis (assessed using 16S rRNA or metagenomic gene sequencing). | Baseline | 
| 1A.iv.6 Intestinal Microbiome (Bacteria) - relative abundances of bacteria | ANCOM analysis (assessed using 16S rRNA or metagenomic gene sequencing). | Change from baseline at 6 months | 
| 1A.iv.12 Intestinal Microbiome (Bacteria) - relative abundances of bacteria | ANCOM analysis (assessed using 16S rRNA or metagenomic gene sequencing). | Change from baseline at 12 months | 
| 1B.i.0 Intestinal Microbiome (Proteome) - normalised abundances of proteins | (assessed using LC-MS). | Baseline | 
| 1B.i.6 Intestinal Microbiome (Proteome) - normalised abundances of proteins | (assessed using LC-MS). | Change from baseline at 6 months | 
| 1B.i.12 Intestinal Microbiome (Proteome) - normalised abundances of proteins | (assessed using LC-MS). | Change from baseline at 12 months | 
| 1C.i.0 Intestinal Microbiome (Metabolome) - normalised abundances of metabolites | (assessed using LC-MS). | Baseline | 
| 1C.i.6 Intestinal Microbiome (Metabolome) - normalised abundances of metabolites | (assessed using LC-MS). | Change from baseline at 6 months | 
| 1C.i.12 Intestinal Microbiome (Metabolome) - normalised abundances of metabolites | (assessed using LC-MS). | Change from baseline at 12 months | 
| 1D.i.0 Intestinal Microbiome (Viruses) - Richness | Measurement of alpha diversity (assessed metagenomic sequencing). | Baseline | 
| 1D.i.6 Intestinal Microbiome (Viruses) - Richness | Measurement of alpha diversity (assessed metagenomic sequencing). | Change from baseline at 6 months | 
| 1D.i.12 Intestinal Microbiome (Viruses) - Richness | Measurement of alpha diversity (assessed metagenomic sequencing). | Change from baseline at 12 months | 
| 1D.ii.0 Intestinal Microbiome (Viruses) - Shannon index | Measurement of alpha diversity (assessed metagenomic sequencing). | Baseline | 
| 1D.ii.6 Intestinal Microbiome (Viruses) - Shannon index | Measurement of alpha diversity (assessed metagenomic sequencing). | Change from baseline at 6 months | 
| 1D.ii.12 Intestinal Microbiome (Viruses) - Shannon index | Measurement of alpha diversity (assessed metagenomic sequencing). | Change from baseline at 12 months | 
| 1D.iii.0 Intestinal Microbiome (Viruses) - Bray-Curtis dissimilarity | Measurement of beta diversity (assessed metagenomic sequencing). | Baseline | 
| 1D.iii.6 Intestinal Microbiome (Viruses) - Bray-Curtis dissimilarity | Measurement of beta diversity (assessed metagenomic sequencing). | 6 months | 
| 1D.iii.12 Intestinal Microbiome (Viruses) - Bray-Curtis dissimilarity | Measurement of beta diversity (assessed metagenomic sequencing). | 12 months | 
| 1D.iv.0 Intestinal Microbiome (Viruses) - relative abundances of viruses. | ANCOM analysis (assessed metagenomic sequencing). | Baseline | 
| 1D.iv.6 Intestinal Microbiome (Viruses) - relative abundances of viruses. | ANCOM analysis (assessed metagenomic sequencing). | Change from baseline at 6 months | 
| 1D.iv.12 Intestinal Microbiome (Viruses) - relative abundances of viruses. | ANCOM analysis (assessed metagenomic sequencing). | Change from baseline at 12 months | 
| 2A.i.0 Respiratory Microbiome (Bacteria) - Richness | Measurement of alpha diversity (assessed using 16S rRNA or metagenomic gene sequencing). | Baseline | 
| 2A.i.6 Respiratory Microbiome (Bacteria) - Richness | Measurement of alpha diversity (assessed using 16S rRNA or metagenomic gene sequencing). | Change from baseline at 6 months | 
| 2A.i.12 Respiratory Microbiome (Bacteria) - Richness | Measurement of alpha diversity (assessed using 16S rRNA or metagenomic gene sequencing). | Change from baseline at 12 months | 
| 2A.ii.0 Respiratory Microbiome (Bacteria) - Shannon index | Measurement of alpha diversity (assessed using 16S rRNA or metagenomic gene sequencing). | Baseline | 
| 2A.ii.6 Respiratory Microbiome (Bacteria) - Shannon index | Measurement of alpha diversity (assessed using 16S rRNA or metagenomic gene sequencing). | Change from baseline at 6 months | 
| 2A.ii.12 Respiratory Microbiome (Bacteria) - Shannon index | Measurement of alpha diversity (assessed using 16S rRNA or metagenomic gene sequencing). | Change from baseline at 12 months | 
| 2A.iii.0 Respiratory Microbiome (Bacteria) - UNIFRAC distances | Measurement of beta diversity (assessed using 16S rRNA or metagenomic gene sequencing). | Baseline | 
| 2A.iii.6 Respiratory Microbiome (Bacteria) - UNIFRAC distances | Measurement of beta diversity (assessed using 16S rRNA or metagenomic gene sequencing). | Change from baseline at 6 months | 
| 2A.iii.12 Respiratory Microbiome (Bacteria) - UNIFRAC distances | Measurement of beta diversity (assessed using 16S rRNA or metagenomic gene sequencing). | Change from baseline at 12 months | 
| 2A.iv.0 Respiratory Microbiome (Bacteria) - relative abundances of bacteria | ANCOM analysis (assessed using 16S rRNA or metagenomic gene sequencing). | Baseline | 
| 2A.iv.6 Respiratory Microbiome (Bacteria) - relative abundances of bacteria | ANCOM analysis (assessed using 16S rRNA or metagenomic gene sequencing). | Change from baseline at 6 months | 
| 2A.iv.12 Respiratory Microbiome (Bacteria) - relative abundances of bacteria | ANCOM analysis (assessed using 16S rRNA or metagenomic gene sequencing). | Change from baseline at 12 months | 
| 2B.i.0 Respiratory Microbiome (Proteome) - normalised abundances of proteins | (assessed using LC-MS). | Baseline | 
| 2B.i.6 Respiratory Microbiome (Proteome) - normalised abundances of proteins | (assessed using LC-MS). | Change from baseline at 6 months | 
| 2B.i.12 Respiratory Microbiome (Proteome) - normalised abundances of proteins | (assessed using LC-MS). | Change from baseline at 12 months | 
| 2C.i.0 Respiratory Microbiome (Metabolome) - normalised abundances of metabolites | (assessed using LC-MS). | Baseline | 
| 2C.i.6 Respiratory Microbiome (Metabolome) - normalised abundances of metabolites | (assessed using LC-MS). | Change from baseline at 6 months | 
| 2C.i.12 Respiratory Microbiome (Metabolome) - normalised abundances of metabolites | (assessed using LC-MS). | Change from baseline at 12 months | 
| 2D.i.0 Respiratory Microbiome (Viruses) - Richness | Measurement of alpha diversity (assessed metagenomic sequencing). | Baseline | 
| 2D.i.6 Respiratory Microbiome (Viruses) - Richness | Measurement of alpha diversity (assessed metagenomic sequencing). | Change from baseline at 6 months | 
| 2D.i.12 Respiratory Microbiome (Viruses) - Richness | Measurement of alpha diversity (assessed metagenomic sequencing). | Change from baseline at 12 months | 
| 2D.ii.0 Respiratory Microbiome (Viruses) - Shannon index | Measurement of alpha diversity (assessed metagenomic sequencing). | Baseline | 
| 2D.ii.6 Respiratory Microbiome (Viruses) - Shannon index | Measurement of alpha diversity (assessed metagenomic sequencing). | Change from baseline at 6 months | 
| 2D.ii.12 Respiratory Microbiome (Viruses) - Shannon index | Measurement of alpha diversity (assessed metagenomic sequencing). | Change from baseline at 12 months | 
| 2D.iii.0 Respiratory Microbiome (Viruses) - Bray-Curtis dissimilarity | Measurement of beta diversity (assessed metagenomic sequencing). | Baseline | 
| 2D.iii.6 Respiratory Microbiome (Viruses) - Bray-Curtis dissimilarity | Measurement of beta diversity (assessed metagenomic sequencing). | 6 months | 
| 2D.iii.12 Respiratory Microbiome (Viruses) - Bray-Curtis dissimilarity | Measurement of beta diversity (assessed metagenomic sequencing). | 12 months | 
| 2D.iv.0 Respiratory Microbiome (Viruses) - relative abundances of viruses | ANCOM analysis (assessed metagenomic sequencing). | Baseline | 
| 2D.iv.6 Respiratory Microbiome (Viruses) - relative abundances of viruses | ANCOM analysis (assessed metagenomic sequencing). | Change from baseline at 6 months | 
| 2D.iv.12 Respiratory Microbiome (Viruses) - relative abundances of viruses | ANCOM analysis (assessed metagenomic sequencing). | Change from baseline at 12 months | 
| 3A.i.0 Diet - total energy intake | Kilojoules (assessed using a 24-hour recall or ACAES). | Baseline | 
| 3A.i.6 Diet - total energy intake | Kilojoules (assessed using a 24-hour recall or ACAES). | Change from baseline at 6 months | 
| 3A.i.12 Diet - total energy intake | Kilojoules (assessed using a 24-hour recall or ACAES). | Change from baseline at 12 months | 
| 3B.i.0 Diet - percentage energy from core foods | (assessed using a 24-hour recall or ACAES). | Baseline | 
| 3B.i.6 Diet - percentage energy from core foods | (assessed using a 24-hour recall or ACAES). | Change from baseline at 6 months | 
| 3B.i.12 Diet - percentage energy from core foods | (assessed using a 24-hour recall or ACAES). | Change from baseline at 12 months | 
| 3C.i.0 Diet - total macronutrients intake | Grams (assessed using a 24-hour recall or ACAES). | Baseline | 
| 3C.i.6 Diet - total macronutrients intake | Grams (assessed using a 24-hour recall or ACAES). | Change from baseline at 6 months | 
| 3C.i.12 Diet - total macronutrients intake | Grams (assessed using a 24-hour recall or ACAES). | Change from baseline at 12 months | 
| 3C.ii.0 Diet - macronutrients proportion of total energy intake | Percentage (assessed using a 24-hour recall or ACAES). | Baseline | 
| 3C.ii.6 Diet - macronutrients proportion of total energy intake | Percentage (assessed using a 24-hour recall or ACAES). | Change from baseline at 6 months | 
| 3C.ii.12 Diet - macronutrients proportion of total energy intake | Percentage (assessed using a 24-hour recall or ACAES). | Change from baseline at 12 months | 
| 3D.i.0 Diet - total micronutrients intake | Milligrams (assessed using a 24-hour recall or ACAES). | Baseline | 
| 3D.i.6 Diet - total micronutrients intake | Milligrams (assessed using a 24-hour recall or ACAES). | Change from baseline at 6 months | 
| 3D.i.12 Diet - total micronutrients intake | Milligrams (assessed using a 24-hour recall or ACAES). | Change from baseline at 12 months | 
| 3D.ii.0 Diet - micronutrients proportion of total energy intake | Percentage (assessed using a 24-hour recall or ACAES). | Baseline | 
| 3D.ii.6 Diet - micronutrients proportion of total energy intake | Percentage (assessed using a 24-hour recall or ACAES). | Change from baseline at 6 months | 
| 3D.ii.12 Diet - micronutrients proportion of total energy intake | Percentage (assessed using a 24-hour recall or ACAES). | Change from baseline at 12 months | 
| 3E.i.0 Diet - diet quality score | Australia recommended food score. Maximum possible score of 73, higher is better (assessed using the ACAES only). | Baseline | 
| 3E.i.6 Diet - diet quality score | Australia recommended food score. Maximum possible score of 73, higher is better (assessed using the ACAES only). | Change from baseline at 6 months | 
| 3E.i.12 Diet - diet quality score | Australia recommended food score. Maximum possible score of 73, higher is better (assessed using the ACAES only). | Change from baseline at 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 4A.i.0 Faecal biomarkers - calprotectin | mg/kg (assessed using an ELISA). | Baseline | 
| 4A.i.6 Faecal biomarkers - calprotectin | mg/kg (assessed using an ELISA). | Change from baseline at 6 months | 
| 4A.i.12 Faecal biomarkers - calprotectin | mg/kg (assessed using an ELISA). | Change from baseline at 12 months | 
| 4A.ii.0 Faecal biomarkers - M2 pyruvate kinase | U/mL (assessed using an ELISA). | Baseline | 
| 4A.ii.6 Faecal biomarkers - M2 pyruvate kinase | U/mL (assessed using an ELISA). | Change from baseline at 6 months | 
| 4A.ii.12 Faecal biomarkers - M2 pyruvate kinase | U/mL (assessed using an ELISA). | Change from baseline at 12 months | 
| 4A.iii.0 Faecal biomarkers - C-reactive protein | mg/L (assessed using an ELISA). | Baseline | 
| 4A.iii.6 Faecal biomarkers - C-reactive protein | mg/L (assessed using an ELISA). | Change from baseline at 6 months | 
| 4A.iii.12 Faecal biomarkers - C-reactive protein | mg/L (assessed using an ELISA). | Change from baseline at 12 months | 
| 4A.iv.0 Faecal biomarkers - Interleukins | IU (assessed using an ELISA). | Baseline | 
| 4A.iv.6 Faecal biomarkers - Interleukins | IU (assessed using an ELISA). | Change from baseline at 6 months | 
| 4A.iv.12 Faecal biomarkers - Interleukins | IU (assessed using an ELISA). | Change from baseline at 12 months | 
| 4B.i.0 Respiratory biomarkers - calprotectin | mg/kg (assessed using an ELISA). | Baseline | 
| 4B.i.6 Respiratory biomarkers - calprotectin | mg/kg (assessed using an ELISA). | Change from baseline at 6 months | 
| 4B.i.12 Respiratory biomarkers - calprotectin | mg/kg (assessed using an ELISA). | Change from baseline at 12 months | 
| 4B.ii.0 Respiratory biomarkers - C-reactive protein | mg/L (assessed using an ELISA). | Baseline | 
| 4B.ii.6 Respiratory biomarkers - C-reactive protein | mg/L (assessed using an ELISA). | Change from baseline at 6 months | 
| 4B.ii.12 Respiratory biomarkers - C-reactive protein | mg/L (assessed using an ELISA). | Change from baseline at 12 months | 
| 4B.iii.0 Respiratory biomarkers - Interleukins | IU (assessed using an ELISA). | Baseline | 
| 4B.iii.6 Respiratory biomarkers - Interleukins | IU (assessed using an ELISA). | Change from baseline at 6 months | 
| 4B.iii.12 Respiratory biomarkers - Interleukins | IU (assessed using an ELISA). | Change from baseline at 12 months | 
| 5A.i.0 Symptomatology & HRQOL - PedsQL Infant Scales (ages 1-12 and 13-24 months) | Parent report for infants (ages 1-12 months) or (ages 13-24 months). Score out of 100, higher scores indicate better HRQOL. | Baseline | 
| 5A.i.6 Symptomatology & HRQOL - PedsQL Infant Scales (ages 1-12 and 13-24 months) | Parent report for infants (ages 1-12 months) or (ages 13-24 months). Score out of 100, higher scores indicate better HRQOL. | Change from baseline at 6 months | 
| 5A.i.12 Symptomatology & HRQOL - PedsQL Infant Scales (ages 1-12 and 13-24 months) | Parent report for infants (ages 1-12 months) or (ages 13-24 months). Score out of 100, higher scores indicate better HRQOL. | Change from baseline at 12 months | 
| 5A.ii.0 Symptomatology & HRQOL - PedsQL Gastrointestinal Symptoms Module (ages 2-4 years) | Parent report for toddlers (ages 2-4 years). Score out of 100, higher scores indicate better HRQOL. | Baseline | 
| 5A.ii.6 Symptomatology & HRQOL - PedsQL Gastrointestinal Symptoms Module (ages 2-4 years) | Parent report for toddlers (ages 2-4 years). Score out of 100, higher scores indicate better HRQOL. | Change from baseline at 6 months | 
| 5A.ii.12 Symptomatology & HRQOL - PedsQL Gastrointestinal Symptoms Module (ages 2-4 years) | Parent report for toddlers (ages 2-4 years). Score out of 100, higher scores indicate better HRQOL. | Change from baseline at 12 months | 
| 5A.iii.0 Symptomatology & HRQOL - PedsQL Gastrointestinal Symptoms Module (ages 5-7 years) | Parent report for young children (ages 5-7 years) or young child report (ages 5-7 years). Score out of 100, higher scores indicate better HRQOL. | Baseline | 
| 5A.iii.6 Symptomatology & HRQOL - PedsQL Gastrointestinal Symptoms Module (ages 5-7 years) | Parent report for young children (ages 5-7 years) or young child report (ages 5-7 years). Score out of 100, higher scores indicate better HRQOL. | Change from baseline at 6 months | 
| 5A.iii.12 Symptomatology & HRQOL - PedsQL Gastrointestinal Symptoms Module (ages 5-7 years) | Parent report for young children (ages 5-7 years) or young child report (ages 5-7 years). Score out of 100, higher scores indicate better HRQOL. | Change from baseline at 12 months | 
| 5A.iv.0 Symptomatology & HRQOL - PedsQL Gastrointestinal Symptoms Module (ages 8-12 years) | Parent report for children (ages 8-12 years) or child report (ages 8-12 years). Score out of 100, higher scores indicate better HRQOL. | Baseline | 
| 5A.iv.6 Symptomatology & HRQOL - PedsQL Gastrointestinal Symptoms Module (ages 8-12 years) | Parent report for children (ages 8-12 years) or child report (ages 8-12 years). Score out of 100, higher scores indicate better HRQOL. | Change from baseline at 6 months | 
| 5A.iv.12 Symptomatology & HRQOL - PedsQL Gastrointestinal Symptoms Module (ages 8-12 years) | Parent report for children (ages 8-12 years) or child report (ages 8-12 years). Score out of 100, higher scores indicate better HRQOL. | Change from baseline at 12 months | 
| 5A.v.0 Symptomatology & HRQOL - PedsQL Gastrointestinal Symptoms Module (ages 13-18 years) | Parent report for teens (ages 13-18 years) or teen report (ages 13-18 years). Score out of 100, higher scores indicate better HRQOL. | Baseline | 
| 5A.v.6 Symptomatology & HRQOL - PedsQL Gastrointestinal Symptoms Module (ages 13-18 years) | Parent report for teens (ages 13-18 years) or teen report (ages 13-18 years). Score out of 100, higher scores indicate better HRQOL. | Change from baseline at 6 months | 
| 5A.v.12 Symptomatology & HRQOL - PedsQL Gastrointestinal Symptoms Module (ages 13-18 years) | Parent report for teens (ages 13-18 years) or teen report (ages 13-18 years). Score out of 100, higher scores indicate better HRQOL. | Change from baseline at 12 months | 
| 5B.i.0 Symptomatology & HRQOL - Rome IV Parent-Report Form for Infants and Toddlers (ages 0-3) | 29 items for ages 0-12 months. 18 items for ages 1-3 years. Defined diagnostic criteria for functional gastrointestinal disorders in neonates and toddlers: Infant regurgitation, Infant rumination syndrome, Cyclic vomiting syndrome, Infant colic, Functional diarrhoea, Infant dyschezia, Functional constipation. | Baseline | 
| 5B.i.6 Symptomatology & HRQOL - Rome IV Parent-Report Form for Infants and Toddlers (ages 0-3) | 29 items for ages 0-12 months. 18 items for ages 1-3 years. Defined diagnostic criteria for functional gastrointestinal disorders in neonates and toddlers: Infant regurgitation, Infant rumination syndrome, Cyclic vomiting syndrome, Infant colic, Functional diarrhoea, Infant dyschezia, Functional constipation. | 6 months | 
| 5B.i.12 Symptomatology & HRQOL - Rome IV Parent-Report Form for Infants and Toddlers (ages 0-3) | 29 items for ages 0-12 months. 18 items for ages 1-3 years. Defined diagnostic criteria for functional gastrointestinal disorders in neonates and toddlers: Infant regurgitation, Infant rumination syndrome, Cyclic vomiting syndrome, Infant colic, Functional diarrhoea, Infant dyschezia, Functional constipation. | 12 months | 
| 5B.ii.0 Symptomatology & HRQOL - Rome IV Parent-Report Form for Children and Adolescents (4 years of age and older) | 42 items. Defined diagnostic criteria for functional gastrointestinal disorders in children and adolescents: Cyclic vomiting syndrome, Functional nausea and functional vomiting, Rumination syndrome, Aerophagia, Functional dyspepsia, Irritable bowel syndrome, Abdominal migraine, Functional abdominal pain - not otherwise specified, Functional Constipation, Nonretentive fecal incontinence. | Baseline | 
| 5B.ii.6 Symptomatology & HRQOL - Rome IV Parent-Report Form for Children and Adolescents (4 years of age and older) | 42 items. Defined diagnostic criteria for functional gastrointestinal disorders in children and adolescents: Cyclic vomiting syndrome, Functional nausea and functional vomiting, Rumination syndrome, Aerophagia, Functional dyspepsia, Irritable bowel syndrome, Abdominal migraine, Functional abdominal pain - not otherwise specified, Functional Constipation, Nonretentive fecal incontinence. | 6 months | 
| 5B.ii.12 Symptomatology & HRQOL - Rome IV Parent-Report Form for Children and Adolescents (4 years of age and older) | 42 items. Defined diagnostic criteria for functional gastrointestinal disorders in children and adolescents: Cyclic vomiting syndrome, Functional nausea and functional vomiting, Rumination syndrome, Aerophagia, Functional dyspepsia, Irritable bowel syndrome, Abdominal migraine, Functional abdominal pain - not otherwise specified, Functional Constipation, Nonretentive fecal incontinence. | 12 months | 
| 5B.iii.0 Symptomatology & HRQOL - Rome IV Self-Report Form for Children and Adolescents (10 years of age and older) | 42 items. Defined diagnostic criteria for functional gastrointestinal disorders in children and adolescents: Cyclic vomiting syndrome, Functional nausea and functional vomiting, Rumination syndrome, Aerophagia, Functional dyspepsia, Irritable bowel syndrome, Abdominal migraine, Functional abdominal pain - not otherwise specified, Functional Constipation, Nonretentive fecal incontinence. | Baseline | 
| 5B.iii.6 Symptomatology & HRQOL - Rome IV Self-Report Form for Children and Adolescents (10 years of age and older) | 42 items. Defined diagnostic criteria for functional gastrointestinal disorders in children and adolescents: Cyclic vomiting syndrome, Functional nausea and functional vomiting, Rumination syndrome, Aerophagia, Functional dyspepsia, Irritable bowel syndrome, Abdominal migraine, Functional abdominal pain - not otherwise specified, Functional Constipation, Nonretentive fecal incontinence. | 6 months | 
| 5B.iii.12 Symptomatology & HRQOL - Rome IV Self-Report Form for Children and Adolescents (10 years of age and older) | 42 items. Defined diagnostic criteria for functional gastrointestinal disorders in children and adolescents: Cyclic vomiting syndrome, Functional nausea and functional vomiting, Rumination syndrome, Aerophagia, Functional dyspepsia, Irritable bowel syndrome, Abdominal migraine, Functional abdominal pain - not otherwise specified, Functional Constipation, Nonretentive fecal incontinence. | 12 months | 
| 5C.i.0 Symptomatology & HRQOL - Spence Children's Anxiety Scale; Preschool Anxiety Scale (Parent report for ages 0 to 4) | 34 items. Maximum possible scores of 112. A score 1 SD above mean for a subscale or total score warrants further clinical investigation. A score of 0.5 SD above the mean on total score is indicative of an elevated, but not clinical level of anxiety. | Baseline | 
| 5C.i.6 Symptomatology & HRQOL - Spence Children's Anxiety Scale; Preschool Anxiety Scale (Parent report for ages 0 to 4) | 34 items. Maximum possible scores of 112. A score 1 SD above mean for a subscale or total score warrants further clinical investigation. A score of 0.5 SD above the mean on total score is indicative of an elevated, but not clinical level of anxiety. | Change from baseline at 6 months | 
| 5C.i.12 Symptomatology & HRQOL - Spence Children's Anxiety Scale; Preschool Anxiety Scale (Parent report for ages 0 to 4) | 34 items. Maximum possible scores of 112. A score 1 SD above mean for a subscale or total score warrants further clinical investigation. A score of 0.5 SD above the mean on total score is indicative of an elevated, but not clinical level of anxiety. | Change from baseline at 12 months | 
| 5C.ii.0 Symptomatology & HRQOL - Spence Children's Anxiety Scale (Parent report for 5 years and older) | 38 scored items. Maximum possible scores of 114. A score 1 SD above mean (T-score of ≥ 60) for a subscale or total score is indicative of subclinical or elevated levels of anxiety warranting further clinical investigation. | Baseline | 
| 5C.ii.6 Symptomatology & HRQOL - Spence Children's Anxiety Scale (Parent report for 5 years and older) | 38 scored items. Maximum possible scores of 114. A score 1 SD above mean (T-score of ≥ 60) for a subscale or total score is indicative of subclinical or elevated levels of anxiety warranting further clinical investigation. | Change from baseline at 6 months | 
| 5C.ii.12 Symptomatology & HRQOL - Spence Children's Anxiety Scale (Parent report for 5 years and older) | 38 scored items. Maximum possible scores of 114. A score 1 SD above mean (T-score of ≥ 60) for a subscale or total score is indicative of subclinical or elevated levels of anxiety warranting further clinical investigation. | Change from baseline at 12 months | 
| 5C.iii.0 Symptomatology & HRQOL - Spence Children's Anxiety Scale (8 years and older) | 38 scored items. Maximum possible scores of 114. A score 1 SD above mean (T-score of ≥ 60) for a subscale or total score is indicative of subclinical or elevated levels of anxiety warranting further clinical investigation. | Baseline | 
| 5C.iii.6 Symptomatology & HRQOL - Spence Children's Anxiety Scale (8 years and older) | 38 scored items. Maximum possible scores of 114. A score 1 SD above mean (T-score of ≥ 60) for a subscale or total score is indicative of subclinical or elevated levels of anxiety warranting further clinical investigation. | Change from baseline at 6 months | 
| 5C.iii.12 Symptomatology & HRQOL - Spence Children's Anxiety Scale (8 years and older) | 38 scored items. Maximum possible scores of 114. A score 1 SD above mean (T-score of ≥ 60) for a subscale or total score is indicative of subclinical or elevated levels of anxiety warranting further clinical investigation. | Change from baseline at 12 months | 
| 5D.i.0 Symptomatology & HRQOL - Mood and Feelings Questionnaire (Short Version) (Parent Report on Child, ages 6-18 years). | 13 items. Maximum possible scores of 26. Higher scores suggest more severe depressive symptoms. A score of ≥ 12 may indicate the presence of depression in the respondent. | Baseline | 
| 5D.i.6 Symptomatology & HRQOL - Mood and Feelings Questionnaire (Short Version) (Parent Report on Child, ages 6-18 years). | 13 items. Maximum possible scores of 26. Higher scores suggest more severe depressive symptoms. A score of ≥ 12 may indicate the presence of depression in the respondent. | Change from baseline at 6 months | 
| 5D.i.12 Symptomatology & HRQOL - Mood and Feelings Questionnaire (Short Version) (Parent Report on Child, ages 6-18 years). | 13 items. Maximum possible scores of 26. Higher scores suggest more severe depressive symptoms. A score of ≥ 12 may indicate the presence of depression in the respondent. | Change from baseline at 12 months | 
| 5D.ii.0 Symptomatology & HRQOL - Mood and Feelings Questionnaire (Short Version) (Child Self Report, ages 6-18 years). | 13 items. Maximum possible scores of 26. Higher scores suggest more severe depressive symptoms. A score of ≥ 12 may indicate the presence of depression in the respondent. | Baseline | 
| 5D.ii.6 Symptomatology & HRQOL - Mood and Feelings Questionnaire (Short Version) (Child Self Report, ages 6-18 years). | 13 items. Maximum possible scores of 26. Higher scores suggest more severe depressive symptoms. A score of ≥ 12 may indicate the presence of depression in the respondent. | Change from baseline at 6 months | 
| 5D.ii.12 Symptomatology & HRQOL - Mood and Feelings Questionnaire (Short Version) (Child Self Report, ages 6-18 years). | 13 items. Maximum possible scores of 26. Higher scores suggest more severe depressive symptoms. A score of ≥ 12 may indicate the presence of depression in the respondent. | Change from baseline at 12 months | 
| 6A.i.0 Phenotypic & Clinical Information - Weight (ages 0 to 20 years) | Z-score. | Baseline | 
| 6A.i.6 Phenotypic & Clinical Information - Weight (ages 0 to 20 years) | Z-score. | Change from baseline at 6 months | 
| 6A.i.12 Phenotypic & Clinical Information - Weight (ages 0 to 20 years) | Z-score. | Change from baseline at 12 months | 
| 6A.ii.0 Phenotypic & Clinical Information - Length (ages 0 to 2 years) | Z-score. | Baseline | 
| 6A.ii.6 Phenotypic & Clinical Information - Length (ages 0 to 2 years) | Z-score. | Change from baseline at 6 months | 
| 6A.ii.12 Phenotypic & Clinical Information - Length (ages 0 to 2 years) | Z-score. | Change from baseline at 12 months | 
| 6A.iii.0 Phenotypic & Clinical Information - Height (ages 2 to 20 years) | Z-score. | Baseline | 
| 6A.iii.6 Phenotypic & Clinical Information - Height (ages 2 to 20 years) | Z-score. | Change from baseline at 6 months | 
| 6A.iii.12 Phenotypic & Clinical Information - Height (ages 2 to 20 years) | Z-score. | Change from baseline at 12 months | 
| 6A.iv.0 Phenotypic & Clinical Information - Weight-for-length (ages 0 to 2 years) | Z-score. | Baseline | 
| 6A.iv.6 Phenotypic & Clinical Information - Weight-for-length (ages 0 to 2 years) | Z-score. | Change from baseline at 6 months | 
| 6A.iv.12 Phenotypic & Clinical Information - Weight-for-length (ages 0 to 2 years) | Z-score. | Change from baseline at 12 months | 
| 6A.v.0 Phenotypic & Clinical Information - Body mass index (ages 2 to 20 years) | Z-score. | Baseline | 
| 6A.v.6 Phenotypic & Clinical Information - Body mass index (ages 2 to 20 years) | Z-score. | Change from baseline at 6 months | 
| 6A.v.12 Phenotypic & Clinical Information - Body mass index (ages 2 to 20 years) | Z-score. | Change from baseline at 12 months | 
| 6B.i.6 Phenotypic & Clinical Information - Number of hospitalisations | During period from baseline to 6 months. | 6 months | 
| 6B.i.12 Phenotypic & Clinical Information - Number of hospitalisations | During period from baseline to 12 months. | 12 months | 
| 6B.ii.6 Phenotypic & Clinical Information - Length of hospitalisations | Days hospitalised during period from baseline to 6 months. | 6 months | 
| 6B.ii.12 Phenotypic & Clinical Information - Length of hospitalisations | Days hospitalised during period from baseline to 12 months. | 12 months | 
| 6B.iii.6 Phenotypic & Clinical Information - Number of emergency department presentations | During period from baseline to 6 months. | 6 months | 
| 6B.iii.12 Phenotypic & Clinical Information - Number of emergency department presentations | During period from baseline to 12 months. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Microbiota, Gastrointestinal Microbiome, Diet, Signs and Symptoms, Quality of Life, Anxiety, Depression