STROBE Statement—checklist of items that should be included in reports of observational studies

	Item No.	Recommendation	Page No.	Relevant text from manuscript
Title and abstract	1	(a) Indicate the study’s design with a commonly used term in the title or the abstract	6	Adults enrolled in a multisite, prospective Consortium of Gastrointestinal Eosinophilic Disease Researchers OMEGA observational study
		(b) Provide in the abstract an informative and balanced summary of what was done and what was found	6	Abstract
Introduction
Background/rationale	2	Explain the scientific background and rationale for the investigation being reported	8	In adults with eosinophilic esophagitis (EoE), esophageal dilation is frequently used to manage symptoms of esophageal dysfunction but does not improve the underlying inflammatory diathesis. For example, using a non-validated physician-reported dysphagia measure in adult EoE patients managed by dilation alone, Schoepfer et al. demonstrated that dysphagia improved for a median of 15 months. These data were corroborated by the results of a patient survey, in which 67% of patients reported that the effect of dilation on symptoms lasted for 12 months or longer. Presently, in randomized clinical trials (RCTs), consideration of the dilation status of enrolled patients is variable. This can be problematic since the effects of dilation on symptoms may be prolonged, and trials are designed to assess improvements in dysphagia in conjunction with improvement in eos/hpf and other biologic markers. Dellon et al. examined the efficacy of budesonide oral suspension in improving symptoms and eos/hpf, and the history of dilation at baseline was not reported. When examining efficacy of budesonide in inducing clinical and histologic remission, Lucendo et al excluded patients with dilation performed within eight weeks of screening.
Objectives	3	State specific objectives, including any prespecified hypotheses	8	Since dilation improves symptoms without any effect on inflammation, we examined long-term effect modification of dilation on the relationship between biologic findings, including centrally read histology, and PROs assessed using validated measures in adult EoE patients
Methods
Study design	4	Present key elements of study design early in the paper	9	Upon entry into the CEGIR OMEGA prospective, multi-center, observational study (ClinicalTrials.gov identification number NCT02523118) AND Cross-sectional data of these patients was analysed for the purposes of this study.
Setting	5	Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data collection	9	…. adults with EoE completed PRO instruments and underwent endoscopy with biopsy sampling between February 2016 and March 2018 in 14 centres across the continental United States.
Participants	6	(a) Cohort study—Give the eligibility criteria, and the sources and methods of selection of participants. Describe methods of follow-up Case-control study—Give the eligibility criteria, and the sources and methods of case ascertainment and control selection. Give the rationale for the choice of cases and controls Cross-sectional study—Give the eligibility criteria, and the sources and methods of selection of participants	9, Supplementary Figure 1	Patients with EoE of 18 years of age or older were eligible. Patients with histology assessment, PRO assessment and known history of dilation were selected for the study.
		(b) Cohort study—For matched studies, give matching criteria and number of exposed and unexposed Case-control study—For matched studies, give matching criteria and the number of controls per case
Variables	7	Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic criteria, if applicable	10	Linear regression analysis in the overall population as well as in the non-dilated patients was performed with EEsAI as the outcome and either eos/hpf or EREFS score as predictors. Residual analysis indicated normality assumptions for the statistical models are appropriate. Given that we hypothesized that dilation might act as an effect modifier (measures of association might be different in the group of patients that were dilated and were not dilated), we included an interaction term for dilation with biologic findings. Dilation was ordered as follows: no dilation (reference category), ≤12 months, and >12 months prior to index endoscopy.
Data sources/ measurement	8*	For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe comparability of assessment methods if there is more than one group	9–10	The description of the way PRO, histology and endoscopy data were collected is described on pages 9/10. The Wilcoxon rank-sum test was used to compare dilated and non-dilated patient groups. The differences in slopes between dilated and non-dilated patients was assessed using linear regression (interaction terms).
Bias	9	Describe any efforts to address potential sources of bias	9–10	The study was prospectively conducted. Validated measures were used to assess all the outcomes of the study (PRO, histology, endoscopy)
Study size	10	Explain how the study size was arrived at	9 Supplementary Figure 1	Patients with histology assessment, PRO assessment and known history of dilation were selected for the study.
Quantitative variables	11	Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and why	10	Quantitative variables were summarized as medians and interquartile ranges. Comparisons between groups were done using Wilcoxon rank-sum test (non-parametric).
Statistical methods	12	(a) Describe all statistical methods, including those used to control for confounding		Non-parametric correlations (Spearman’s rho) and linear regression were used. Dilation groups were ordered as follows: no dilation (reference category for linear regression), ≤12 months, and >12 months prior to index endoscopy.
		(b) Describe any methods used to examine subgroups and interactions		Linear regression was used. The interaction of dilation and either eos/hpf or EREFS was examined.
		(c) Explain how missing data were addressed		No data imputation was used for missing values of outcome measures.
		(d) Cohort study—If applicable, explain how loss to follow-up was addressed Case-control study—If applicable, explain how matching of cases and controls was addressed Cross-sectional study—If applicable, describe analytical methods taking account of sampling strategy		Not applicable.
		(e) Describe any sensitivity analyses		Residual analysis indicated normality assumptions for the statistical models are appropriate.
Results
Participants	13*	(a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analysed	12, Supplementary Figure 1	Of the 392 patients, 176 had baseline histologic assessment, 122 completed EEsAI PRO. Of the 122, 100 had a history of dilation. Of the 100 patients with EEsAI PRO, 96 patients completed EoE-QoL-A instrument.
		(b) Give reasons for non-participation at each stage	12	Lack of data.
		(c) Consider use of a flow diagram	12, Supplementary Figure 1	The flow diagram is provided in Supplementary Figure 1.
Descriptive data	14*	(a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential confounders	12, Table 1	Provided in table 1 and discussed in subsection Patient characteristic of the Results section
		(b) Indicate number of participants with missing data for each variable of interest	Supplementary Figure 1	216 were missing central histology assessment at the time of the start of the analyses 54 patients were missing EEsAI PRO completion 22 patients were missing the history of dilation 4 patients were missing EoE-QoL-A
		(c) Cohort study—Summarise follow-up time (eg, average and total amount)		NA
Outcome data	15*	Cohort study—Report numbers of outcome events or summary measures over time		NA
		Case-control study—Report numbers in each exposure category, or summary measures of exposure		NA
		Cross-sectional study—Report numbers of outcome events or summary measures	12–15	100 outcomes events (EEsAI PRO as outcome)
Main results	16	(a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, 95% confidence interval). Make clear which confounders were adjusted for and why they were included	12–15	Slope estimates (regression coefficients), interaction term esitimates and their 95% confidence intervals were provided.
		(b) Report category boundaries when continuous variables were categorized	12, Table1	Interquartile ranges were provided for continuous variables
		(c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period		NA
Other analyses	17	Report other analyses done—eg analyses of subgroups and interactions, and sensitivity analyses		Not applicable
Discussion
Key results	18	Summarise key results with reference to study objectives	16	In this observational cohort study of adult patients with EoE, we found that dilation performed within 12 months of the index endoscopy modifies the relationship between biologic findings and symptom severity as assessed by EEsAI. In non-dilated patients, we identified a statistically significant moderate positive association between eos/hpf and symptom severity. The association tended negative in patients dilated within 12 months of index endoscopy, although it did not reach statistical significance. Similarly, we found a positive weak correlation between EREFS and symptom severity in non-dilated patients that did not reach statistical significance but a statistically significant negative moderate association between these parameters in patients dilated ≤12 months prior to index endoscopy. No association between symptoms and biologic findings was observed in patients that were dilated > 12 months prior to index endoscopy. Overall, the direction of the associations between symptoms and biologic findings was consistent irrespective of whether the relationship between symptoms and eos/hpf or symptoms and EREFS was examined. In non-dilated patients, variation in maximum of proximal and distal eos/hpf explained 19% of the variation in symptom severity. Given that dilation modifies the relationship between symptoms and biologic findings, consideration should be given to the impact of dilation on symptom assessment both in therapeutic studies and clinical practice.
Limitations	19	Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and magnitude of any potential bias	18	Our results should be interpreted with a number of considerations in mind. We observed no significant modification of the slope and, therefore, the relationship between EoE-specific quality of life and biologic findings based on dilation status. Therefore, larger studies are needed to examine whether dilation modifies the association between EoE-QoL-A and biologic findings. We observed a negative association, when we examined the relationship between symptoms and biologic findings in 15 patients dilated ≤12 months prior to index endoscopy. Given the relatively small sample size, we were not able to adjust for confounding, such as the use of anti-inflammatory therapies and duration of treatment, and other factors responsible for symptom variation in EoE patients. In addition, only limited information about dilation characteristics was collected. Therefore, reasons for this negative association remain unexplained and larger studies are needed to elucidate the nature of the relationship between symptoms and biologic findings in recently dilated individuals.
Interpretation	20	Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence	16–18	In conclusion, dilation modifies the association between histologic activity and symptom severity, and the effects of dilation last for longer than 12 months. In non-dilated patients, the strength of the positive association between eos/hpf and symptom score was moderate, while no statistically significant association was observed in patients dilated prior to index endoscopy. The results of the current study in part corroborate the finding by Schoepfer and colleagues that previously showed that the effects of the dilation likely last approximately 12 months in adults with EoE (ref 2). In a secondary analyses of data from a RCT comparing oral viscous budesonide and fluticasone in a multi-dose inhaler in newly diagnosed EoE patients, Safroneeva et al. recently found that dilation performed ≤3 months prior to symptom assessment not only modifies the association between baseline eos/hpf and symptom severity (findings corroborated by this study), but also modifies the association between the change from baseline to end of treatment in eos/hpf and symptom severity (ref 10)
Generalisability	21	Discuss the generalisability (external validity) of the study results	18	Based on these findings, we suggest that futures studies evaluating treatments for EoE should consider dilation status, and, where appropriate, make decisions regarding stratified randomization in the context of the planned sample size. In addition, characteristics of the study population in terms of stricture prevalence should be considered, especially when demonstrating symptom improvement in conjunction with improvement in eos/hpf is of interest. In clinical practice, symptoms should not be used to monitor the benefit of medical treatments in patients that underwent dilation within at least 12 months prior to index endoscopy.
Other information
Funding	22	Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on which the present article is based	4	CEGIR (U54 AI117804) is part of the Rare Disease Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), NCATS, and is funded through collaboration between NIAID, NIDDK, and NCATS. CEGIR is also supported by patient advocacy groups including American Partnership for Eosinophilic Disorders (APFED), Campaign Urging Research for Eosinophilic Diseases (CURED), and Eosinophilic Family Coalition (EFC). As a member of the RDCRN, CEGIR is also supported by its Data Management and Coordinating Center (DMCC) (U2CTR002818). This work is also supported by a grant given to Ekaterina Safroneeva by Swiss National Science Foundation (Project number: 32473B_185008). La Cache Chair for GI Allergy and Immunology Research (GTF).

^*Give information separately for cases and controls in case-control studies and, if applicable, for exposed and unexposed groups in cohort and cross-sectional studies.

^Note:An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is available at www.strobe-statement.org.