Long-Term Outcomes of Esophageal Atresia: Transomic Profiles in Adolescence FReSH-43727-en Mélanie LEROY Long-Term Outcomes of Esophageal Atresia: Transomic Profiles in Adolescence TransEAsome FReSH-43727-en Frédéric GOTTRAND CENTRE HOSPITALIER UNIVERSITAIRE DE LILLE (CHU) France Recherche en Santé Humaine (FReSH) AGENCE NATIONALE DE LA RECHERCHE (ANR) null Mélanie;LEROY Martin;FIGEAC Michel;SALZET Jimmy;VANDEL Régis;HANKARD CNIL CPP esophageal atresia pediatrics cohort omic Gastroenterology Paediatrics Atresia of oesophagus Atresia of oesophagus without fistula Atresia of oesophagus with tracheo-oesophageal fistula Long gap oesophageal atresia Atresia of oesophagus with oesophagobronchial fistula Atresia of oesophagus with fistula between trachea and lower oesophageal pouch Atresia of oesophagus with fistula between trachea and upper oesophageal pouch Atresia of oesophagus with fistula between trachea and oesophageal pouch Socio-demographic and economic determinants Socio-demographic and economic determinants: Gender Socio-demographic and economic determinants: Age Healthcare system determinants Healthcare system determinants: Use of care Behavioral determinants Behavioral determinants: Physical activity Behavioral determinants: Hygiene Biological determinants Biological determinants: Sex Other proteins, methylation, microRNA 2.1 Main Objective 1. Assess the prevalence of gastroesophageal reflux (GERD) [pH/impedance monitoring indicating pathological GERD and/or if lesions of peptic esophagitis are observed during an endoscopy in the year prior to the visit, or if the child has a history of complicated GERD that led to anti-reflux surgery] during adolescence (ages 13–14) in children born with esophageal atresia 2.2 Secondary Objectives The study has several secondary objectives: 1. Identify the factors measured throughout the patient’s follow-up (at birth, 1 year, 6 years, and 13–14 years) that are associated with the prevalence of GERD in adolescence among children born with esophageal atresia 2. Assessing quality of life, nutritional status, and the frequency of respiratory complications in adolescents who were born with esophageal atresia In patients who underwent an esophageal biopsy at ages 10–14 3. Analyze the omic and multi-omic profiles derived from esophageal biopsies in these patients during adolescence—in comparison with a control group of adolescents without esophageal atresia—to identify disruptions in biological pathways associated with esophageal atresia in patients who have had multiple biopsies since birth 4. Examine changes in the expression levels of omic variables in the biological pathways identified in OS3 over time Among patients who underwent blood tests and esophageal biopsies at ages 10–14 (a substudy conducted at centers in Lille, Paris Necker, Paris Robert Debré, Lyon, Grenoble, and Marseille) 5. To investigate the correlation between plasma levels of microRNAs or proteins and those measured in esophageal biopsies in relation to the omics variables identified in OS3. Esophageal atresia (EA), a congenital malformation of the esophagus present at birth, is characterized by a disruption in the continuity of the esophagus, which ends in a blind pouch. Food or saliva cannot pass into the stomach. It affects an average of 150 births per year in France, making it a rare condition. It is therefore necessary to perform surgery to restore continuity of the esophagus. Although this procedure allows the vast majority of children to survive the neonatal period, health problems such as gastroesophageal reflux, difficulty eating, respiratory problems, and growth issues may persist throughout their lives. Project Objectives The goal of the project is to establish a prospective cohort of 13- and 14-year-old adolescents, nested within the national esophageal atresia registry. In addition to clinical data, a biobank of esophageal mucosal and plasma samples will be established. Once the clinical data have been collected and the omics data (derived from the analysis of biological samples from the biobank) have been generated, they will be analyzed by the project partners to assess the long-term course of EA and establish multi-omics profiles. France Auvergne Rhône-Alpes Bourgogne Franche-Comté Bretagne Centre-Val de Loire Corse Grand Est Guadeloupe Hauts-de-France Ile-de-France La Réunion Martinique Normandie Nouvelle-Aquitaine Occitanie Pays de la Loire Provence - Alpes - Côte d'Azur Individus Patients population Female Male Prenatal Infant, Newborn (birth to 28 days) Infant (28 days to 2 years) Child (6 to 12 years) Adolescent (13 to 18 years) For the EA group: - Born with esophageal atresia (EA) in France or in the French overseas departments and territories (DOM/TOM) - Esophageal anastomosis performed - Must be 13 or 14 years old during the recruitment period (2023–2026) - Enrollment in the Renato Registry - Patient covered by social security - A patient willing to comply with all study procedures and to participate for the duration of the study For the blood substudy: - Upper gastrointestinal endoscopy performed as part of medical care between the ages of 10 and 14, with a biopsy of the esophageal mucosa - Patient who has provided written consent to participate in the study (or in the ancillary study, if applicable, for the centers in Lille, Paris Necker, Paris Robert Debré, Lyon, Marseille, and Grenoble) For the control group: - Upper gastrointestinal endoscopy performed between the ages of 10 and 14, with a biopsy of the esophageal mucosa - Upper gastrointestinal endoscopy performed as part of the management of chronic or acute gastrointestinal symptoms to rule out an organic cause (peptic esophagitis, gastric esophagitis, eosinophilic esophagitis or ulcer) - Normal endoscopy and histology - No concurrent progressive chronic disease Exclusion Criteria For the EA group: - Concurrent participation in an interventional trial as well as within 3 the month prior to inclusion - Parents who refuse to participate in the study For the control group: - Esophageal biopsy with histologically abnormal findings - Parents who refuse to participate in the study - Child with a known organic condition Clinical data Biological data Socio-demographic data Economic data Other Steering Committee and Scientific Advisory Board GERD will be suspected in the presence of suggestive symptoms such as regurgitation and heartburn. The diagnosis will be confirmed if, within the year prior to the visit, a pH/impedance study reveals pathological GERD and/or if lesions of peptic esophagitis are observed during endoscopy, or if the child has a history of complicated GERD that led to anti-reflux surgery. GERD will be considered absent in the absence of clinical signs of GERD (regurgitation, heartburn) and if the most recent pH/impedance monitoring performed without treatment as part of follow-up does not reveal pathological GERD. Assignment No. 1: Variable to be explained (dependent variable): the prevalence of GERD at ages 13–14 Explanatory (independent) variables: These will be identified from the patients’ characteristics at birth, at 1 year, 6 years, and 13–14 years of age (prenatal data, vital signs, presence of associated malformations, type of atresia, surgical procedures performed, surgical/gastrointestinal/respiratory/neuroorthopedic complications, feeding method, and educational attainment). OS No. 2: - The quality of life of adolescent patients will be assessed by administering the following quality-of-life scales when the patients are 13–14 years old: PedsQL and EA-QoL, to be completed by both the patient and a parent. The scale scores will be calculated in accordance with the authors’ administration guidelines. - Nutritional status will be assessed based on weight and height, as well as by calculating the weight-for-height z-score and BMI z-score, using the World Health Organization’s growth charts as a reference. - Frequency of respiratory complications, as assessed during the clinical examination (hoarse cough during infections, chronic cough, asthma, exercise-induced symptoms [cough, dyspnea], atopy, wheezing, and/or stridor). OS No. 3 Measured variables: transcripts, metabolites, proteins, and methylation Variables to be explained (dependent variables): EA diagnosis (yes/no) The affected metabolic pathways will be identified through enrichment analysis based on the markers that are dysregulated between the group with EA and the group without EA. OS No. 4: Measured variables: transcripts, metabolites, proteins, and methylation Analysis of the difference in means between the levels of the measured variables at different time points OS No. 5: Variables measured in plasma: expression levels of microRNAs or proteins Variables measured in esophageal biopsies: expression levels of microRNAs or proteins. The statistical unit will be the omic variable (microRNA or protein), and the correlation will be calculated between the measurements in plasma and the corresponding measurements in the biopsies. Other Once Complete enumeration (including consecutive recruitment) Disease and death registry < 500 individuals Interview with the participant (including clinical) Measurements and tests Physical/biological measurements (blood pressure, weight, biochemistry, imaging, etc.) Psychological tests/clinical scales (depression, cognition, quality of life, etc.) Observation (clinical or behavioural) Self-administered questionnaire National Registry of Patients Born with Esophageal Atresia in France ReNAtO Data enrichment through cross-referencing Registry Observational Study Observational Study Cohort study 413 Ongoing study To be defined Mélanie;LEROY