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

Healthy Clinical Trial

— EARTH  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04071314
• Other study ID #: HREC/18/SCHN/26
• Status: Recruiting
• Start date: April 18, 2018
• Est. completion date: March 13, 2023

Study information

• Verified date: August 2019
• Source: The University of New South Wales
• Contact: Michael J Coffey
• Phone: 61293825574
• Email: michael.coffey[@]unsw.edu.au
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

Description:

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:

1. Known inflammatory biomarkers.

2. Symptomatology and health-related quality of life (HRQOL) using validated measures.

3. Phenotypic and clinical information.

4. 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 72
• Est. completion date: March 13, 2023
• Est. primary completion date: March 13, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: N/A to 18 Years

Eligibility

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.

Related Conditions & MeSH terms

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

Locations

Country	Name	City	State
Australia	Sydney Children's Hospital	Randwick	New South Wales

Sponsors (1)

Lead Sponsor	Collaborator
The University of New South Wales

Country where clinical trial is conducted

Australia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	1A.i.0 Intestinal Microbiome (Bacteria) - Richness	Measurement of alpha diversity (assessed using 16S rRNA or metagenomic gene sequencing).	Baseline
Primary	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
Primary	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
Primary	1A.ii.0 Intestinal Microbiome (Bacteria) - Shannon index	Measurement of alpha diversity (assessed using 16S rRNA or metagenomic gene sequencing).	Baseline
Primary	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
Primary	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
Primary	1A.iii.0 Intestinal Microbiome (Bacteria) - UNIFRAC distances	Measurement of beta diversity (assessed using 16S rRNA or metagenomic gene sequencing).	Baseline
Primary	1A.iii.6 Intestinal Microbiome (Bacteria) - UNIFRAC distances	Measurement of beta diversity (assessed using 16S rRNA or metagenomic gene sequencing).	6 months
Primary	1A.iii.12 Intestinal Microbiome (Bacteria) - UNIFRAC distances	Measurement of beta diversity (assessed using 16S rRNA or metagenomic gene sequencing).	12 months
Primary	1A.iv.0 Intestinal Microbiome (Bacteria) - relative abundances of bacteria	ANCOM analysis (assessed using 16S rRNA or metagenomic gene sequencing).	Baseline
Primary	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
Primary	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
Primary	1B.i.0 Intestinal Microbiome (Proteome) - normalised abundances of proteins	(assessed using LC-MS).	Baseline
Primary	1B.i.6 Intestinal Microbiome (Proteome) - normalised abundances of proteins	(assessed using LC-MS).	Change from baseline at 6 months
Primary	1B.i.12 Intestinal Microbiome (Proteome) - normalised abundances of proteins	(assessed using LC-MS).	Change from baseline at 12 months
Primary	1C.i.0 Intestinal Microbiome (Metabolome) - normalised abundances of metabolites	(assessed using LC-MS).	Baseline
Primary	1C.i.6 Intestinal Microbiome (Metabolome) - normalised abundances of metabolites	(assessed using LC-MS).	Change from baseline at 6 months
Primary	1C.i.12 Intestinal Microbiome (Metabolome) - normalised abundances of metabolites	(assessed using LC-MS).	Change from baseline at 12 months
Primary	1D.i.0 Intestinal Microbiome (Viruses) - Richness	Measurement of alpha diversity (assessed metagenomic sequencing).	Baseline
Primary	1D.i.6 Intestinal Microbiome (Viruses) - Richness	Measurement of alpha diversity (assessed metagenomic sequencing).	Change from baseline at 6 months
Primary	1D.i.12 Intestinal Microbiome (Viruses) - Richness	Measurement of alpha diversity (assessed metagenomic sequencing).	Change from baseline at 12 months
Primary	1D.ii.0 Intestinal Microbiome (Viruses) - Shannon index	Measurement of alpha diversity (assessed metagenomic sequencing).	Baseline
Primary	1D.ii.6 Intestinal Microbiome (Viruses) - Shannon index	Measurement of alpha diversity (assessed metagenomic sequencing).	Change from baseline at 6 months
Primary	1D.ii.12 Intestinal Microbiome (Viruses) - Shannon index	Measurement of alpha diversity (assessed metagenomic sequencing).	Change from baseline at 12 months
Primary	1D.iii.0 Intestinal Microbiome (Viruses) - Bray-Curtis dissimilarity	Measurement of beta diversity (assessed metagenomic sequencing).	Baseline
Primary	1D.iii.6 Intestinal Microbiome (Viruses) - Bray-Curtis dissimilarity	Measurement of beta diversity (assessed metagenomic sequencing).	6 months
Primary	1D.iii.12 Intestinal Microbiome (Viruses) - Bray-Curtis dissimilarity	Measurement of beta diversity (assessed metagenomic sequencing).	12 months
Primary	1D.iv.0 Intestinal Microbiome (Viruses) - relative abundances of viruses.	ANCOM analysis (assessed metagenomic sequencing).	Baseline
Primary	1D.iv.6 Intestinal Microbiome (Viruses) - relative abundances of viruses.	ANCOM analysis (assessed metagenomic sequencing).	Change from baseline at 6 months
Primary	1D.iv.12 Intestinal Microbiome (Viruses) - relative abundances of viruses.	ANCOM analysis (assessed metagenomic sequencing).	Change from baseline at 12 months
Primary	2A.i.0 Respiratory Microbiome (Bacteria) - Richness	Measurement of alpha diversity (assessed using 16S rRNA or metagenomic gene sequencing).	Baseline
Primary	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
Primary	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
Primary	2A.ii.0 Respiratory Microbiome (Bacteria) - Shannon index	Measurement of alpha diversity (assessed using 16S rRNA or metagenomic gene sequencing).	Baseline
Primary	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
Primary	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
Primary	2A.iii.0 Respiratory Microbiome (Bacteria) - UNIFRAC distances	Measurement of beta diversity (assessed using 16S rRNA or metagenomic gene sequencing).	Baseline
Primary	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
Primary	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
Primary	2A.iv.0 Respiratory Microbiome (Bacteria) - relative abundances of bacteria	ANCOM analysis (assessed using 16S rRNA or metagenomic gene sequencing).	Baseline
Primary	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
Primary	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
Primary	2B.i.0 Respiratory Microbiome (Proteome) - normalised abundances of proteins	(assessed using LC-MS).	Baseline
Primary	2B.i.6 Respiratory Microbiome (Proteome) - normalised abundances of proteins	(assessed using LC-MS).	Change from baseline at 6 months
Primary	2B.i.12 Respiratory Microbiome (Proteome) - normalised abundances of proteins	(assessed using LC-MS).	Change from baseline at 12 months
Primary	2C.i.0 Respiratory Microbiome (Metabolome) - normalised abundances of metabolites	(assessed using LC-MS).	Baseline
Primary	2C.i.6 Respiratory Microbiome (Metabolome) - normalised abundances of metabolites	(assessed using LC-MS).	Change from baseline at 6 months
Primary	2C.i.12 Respiratory Microbiome (Metabolome) - normalised abundances of metabolites	(assessed using LC-MS).	Change from baseline at 12 months
Primary	2D.i.0 Respiratory Microbiome (Viruses) - Richness	Measurement of alpha diversity (assessed metagenomic sequencing).	Baseline
Primary	2D.i.6 Respiratory Microbiome (Viruses) - Richness	Measurement of alpha diversity (assessed metagenomic sequencing).	Change from baseline at 6 months
Primary	2D.i.12 Respiratory Microbiome (Viruses) - Richness	Measurement of alpha diversity (assessed metagenomic sequencing).	Change from baseline at 12 months
Primary	2D.ii.0 Respiratory Microbiome (Viruses) - Shannon index	Measurement of alpha diversity (assessed metagenomic sequencing).	Baseline
Primary	2D.ii.6 Respiratory Microbiome (Viruses) - Shannon index	Measurement of alpha diversity (assessed metagenomic sequencing).	Change from baseline at 6 months
Primary	2D.ii.12 Respiratory Microbiome (Viruses) - Shannon index	Measurement of alpha diversity (assessed metagenomic sequencing).	Change from baseline at 12 months
Primary	2D.iii.0 Respiratory Microbiome (Viruses) - Bray-Curtis dissimilarity	Measurement of beta diversity (assessed metagenomic sequencing).	Baseline
Primary	2D.iii.6 Respiratory Microbiome (Viruses) - Bray-Curtis dissimilarity	Measurement of beta diversity (assessed metagenomic sequencing).	6 months
Primary	2D.iii.12 Respiratory Microbiome (Viruses) - Bray-Curtis dissimilarity	Measurement of beta diversity (assessed metagenomic sequencing).	12 months
Primary	2D.iv.0 Respiratory Microbiome (Viruses) - relative abundances of viruses	ANCOM analysis (assessed metagenomic sequencing).	Baseline
Primary	2D.iv.6 Respiratory Microbiome (Viruses) - relative abundances of viruses	ANCOM analysis (assessed metagenomic sequencing).	Change from baseline at 6 months
Primary	2D.iv.12 Respiratory Microbiome (Viruses) - relative abundances of viruses	ANCOM analysis (assessed metagenomic sequencing).	Change from baseline at 12 months
Primary	3A.i.0 Diet - total energy intake	Kilojoules (assessed using a 24-hour recall or ACAES).	Baseline
Primary	3A.i.6 Diet - total energy intake	Kilojoules (assessed using a 24-hour recall or ACAES).	Change from baseline at 6 months
Primary	3A.i.12 Diet - total energy intake	Kilojoules (assessed using a 24-hour recall or ACAES).	Change from baseline at 12 months
Primary	3B.i.0 Diet - percentage energy from core foods	(assessed using a 24-hour recall or ACAES).	Baseline
Primary	3B.i.6 Diet - percentage energy from core foods	(assessed using a 24-hour recall or ACAES).	Change from baseline at 6 months
Primary	3B.i.12 Diet - percentage energy from core foods	(assessed using a 24-hour recall or ACAES).	Change from baseline at 12 months
Primary	3C.i.0 Diet - total macronutrients intake	Grams (assessed using a 24-hour recall or ACAES).	Baseline
Primary	3C.i.6 Diet - total macronutrients intake	Grams (assessed using a 24-hour recall or ACAES).	Change from baseline at 6 months
Primary	3C.i.12 Diet - total macronutrients intake	Grams (assessed using a 24-hour recall or ACAES).	Change from baseline at 12 months
Primary	3C.ii.0 Diet - macronutrients proportion of total energy intake	Percentage (assessed using a 24-hour recall or ACAES).	Baseline
Primary	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
Primary	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
Primary	3D.i.0 Diet - total micronutrients intake	Milligrams (assessed using a 24-hour recall or ACAES).	Baseline
Primary	3D.i.6 Diet - total micronutrients intake	Milligrams (assessed using a 24-hour recall or ACAES).	Change from baseline at 6 months
Primary	3D.i.12 Diet - total micronutrients intake	Milligrams (assessed using a 24-hour recall or ACAES).	Change from baseline at 12 months
Primary	3D.ii.0 Diet - micronutrients proportion of total energy intake	Percentage (assessed using a 24-hour recall or ACAES).	Baseline
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	4A.i.0 Faecal biomarkers - calprotectin	mg/kg (assessed using an ELISA).	Baseline
Secondary	4A.i.6 Faecal biomarkers - calprotectin	mg/kg (assessed using an ELISA).	Change from baseline at 6 months
Secondary	4A.i.12 Faecal biomarkers - calprotectin	mg/kg (assessed using an ELISA).	Change from baseline at 12 months
Secondary	4A.ii.0 Faecal biomarkers - M2 pyruvate kinase	U/mL (assessed using an ELISA).	Baseline
Secondary	4A.ii.6 Faecal biomarkers - M2 pyruvate kinase	U/mL (assessed using an ELISA).	Change from baseline at 6 months
Secondary	4A.ii.12 Faecal biomarkers - M2 pyruvate kinase	U/mL (assessed using an ELISA).	Change from baseline at 12 months
Secondary	4A.iii.0 Faecal biomarkers - C-reactive protein	mg/L (assessed using an ELISA).	Baseline
Secondary	4A.iii.6 Faecal biomarkers - C-reactive protein	mg/L (assessed using an ELISA).	Change from baseline at 6 months
Secondary	4A.iii.12 Faecal biomarkers - C-reactive protein	mg/L (assessed using an ELISA).	Change from baseline at 12 months
Secondary	4A.iv.0 Faecal biomarkers - Interleukins	IU (assessed using an ELISA).	Baseline
Secondary	4A.iv.6 Faecal biomarkers - Interleukins	IU (assessed using an ELISA).	Change from baseline at 6 months
Secondary	4A.iv.12 Faecal biomarkers - Interleukins	IU (assessed using an ELISA).	Change from baseline at 12 months
Secondary	4B.i.0 Respiratory biomarkers - calprotectin	mg/kg (assessed using an ELISA).	Baseline
Secondary	4B.i.6 Respiratory biomarkers - calprotectin	mg/kg (assessed using an ELISA).	Change from baseline at 6 months
Secondary	4B.i.12 Respiratory biomarkers - calprotectin	mg/kg (assessed using an ELISA).	Change from baseline at 12 months
Secondary	4B.ii.0 Respiratory biomarkers - C-reactive protein	mg/L (assessed using an ELISA).	Baseline
Secondary	4B.ii.6 Respiratory biomarkers - C-reactive protein	mg/L (assessed using an ELISA).	Change from baseline at 6 months
Secondary	4B.ii.12 Respiratory biomarkers - C-reactive protein	mg/L (assessed using an ELISA).	Change from baseline at 12 months
Secondary	4B.iii.0 Respiratory biomarkers - Interleukins	IU (assessed using an ELISA).	Baseline
Secondary	4B.iii.6 Respiratory biomarkers - Interleukins	IU (assessed using an ELISA).	Change from baseline at 6 months
Secondary	4B.iii.12 Respiratory biomarkers - Interleukins	IU (assessed using an ELISA).	Change from baseline at 12 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	6A.i.0 Phenotypic & Clinical Information - Weight (ages 0 to 20 years)	Z-score.	Baseline
Secondary	6A.i.6 Phenotypic & Clinical Information - Weight (ages 0 to 20 years)	Z-score.	Change from baseline at 6 months
Secondary	6A.i.12 Phenotypic & Clinical Information - Weight (ages 0 to 20 years)	Z-score.	Change from baseline at 12 months
Secondary	6A.ii.0 Phenotypic & Clinical Information - Length (ages 0 to 2 years)	Z-score.	Baseline
Secondary	6A.ii.6 Phenotypic & Clinical Information - Length (ages 0 to 2 years)	Z-score.	Change from baseline at 6 months
Secondary	6A.ii.12 Phenotypic & Clinical Information - Length (ages 0 to 2 years)	Z-score.	Change from baseline at 12 months
Secondary	6A.iii.0 Phenotypic & Clinical Information - Height (ages 2 to 20 years)	Z-score.	Baseline
Secondary	6A.iii.6 Phenotypic & Clinical Information - Height (ages 2 to 20 years)	Z-score.	Change from baseline at 6 months
Secondary	6A.iii.12 Phenotypic & Clinical Information - Height (ages 2 to 20 years)	Z-score.	Change from baseline at 12 months
Secondary	6A.iv.0 Phenotypic & Clinical Information - Weight-for-length (ages 0 to 2 years)	Z-score.	Baseline
Secondary	6A.iv.6 Phenotypic & Clinical Information - Weight-for-length (ages 0 to 2 years)	Z-score.	Change from baseline at 6 months
Secondary	6A.iv.12 Phenotypic & Clinical Information - Weight-for-length (ages 0 to 2 years)	Z-score.	Change from baseline at 12 months
Secondary	6A.v.0 Phenotypic & Clinical Information - Body mass index (ages 2 to 20 years)	Z-score.	Baseline
Secondary	6A.v.6 Phenotypic & Clinical Information - Body mass index (ages 2 to 20 years)	Z-score.	Change from baseline at 6 months
Secondary	6A.v.12 Phenotypic & Clinical Information - Body mass index (ages 2 to 20 years)	Z-score.	Change from baseline at 12 months
Secondary	6B.i.6 Phenotypic & Clinical Information - Number of hospitalisations	During period from baseline to 6 months.	6 months
Secondary	6B.i.12 Phenotypic & Clinical Information - Number of hospitalisations	During period from baseline to 12 months.	12 months
Secondary	6B.ii.6 Phenotypic & Clinical Information - Length of hospitalisations	Days hospitalised during period from baseline to 6 months.	6 months
Secondary	6B.ii.12 Phenotypic & Clinical Information - Length of hospitalisations	Days hospitalised during period from baseline to 12 months.	12 months
Secondary	6B.iii.6 Phenotypic & Clinical Information - Number of emergency department presentations	During period from baseline to 6 months.	6 months
Secondary	6B.iii.12 Phenotypic & Clinical Information - Number of emergency department presentations	During period from baseline to 12 months.	12 months