Twin and family studies reveal strong environmental and weaker genetic cues explaining heritability of eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic antigen-driven allergic inflammatory disease, likely involving the interplay of genetic and environmental factors, yet their respective contributions to heritability are unknown. OBJECTIVE: To quantify the risk associated with genes and environment on familial clustering of EoE. METHODS: Family history was obtained from a hospital-based cohort of 914 EoE probands (n = 2192 first-degree "Nuclear-Family" relatives) and an international registry of monozygotic and dizygotic twins/triplets (n = 63 EoE "Twins" probands). Frequencies, recurrence risk ratios (RRRs), heritability, and twin concordance were estimated. Environmental exposures were preliminarily examined. RESULTS: Analysis of the Nuclear-Family-based cohort revealed that the rate of EoE, in first-degree relatives of a proband, was 1.8% (unadjusted) and 2.3% (sex-adjusted). RRRs ranged from 10 to 64, depending on the family relationship, and were higher in brothers (64.0; P = .04), fathers (42.9; P = .004), and males (50.7; P < .001) than in sisters, mothers, and females, respectively. The risk of EoE for other siblings was 2.4%. In the Nuclear-Family cohort, combined gene and common environment heritability was 72.0% ± 2.7% (P < .001). In the Twins cohort, genetic heritability was 14.5% ± 4.0% (P < .001), and common family environment contributed 81.0% ± 4% (P < .001) to phenotypic variance. Probandwise concordance in monozygotic co-twins was 57.9% ± 9.5% compared with 36.4% ± 9.3% in dizygotic co-twins (P = .11). Greater birth weight difference between twins (P = .01), breast-feeding (P = .15), and fall birth season (P = .02) were associated with twin discordance in disease status. CONCLUSIONS: EoE RRRs are increased 10- to 64-fold compared with the general population. EoE in relatives is 1.8% to 2.4%, depending on relationship and sex. Nuclear-Family heritability appeared to be high (72.0%). However, the Twins cohort analysis revealed a powerful role for common environment (81.0%) compared with additive genetic heritability (14.5%).

PedsQL eosinophilic esophagitis module: feasibility, reliability, and validity.

OBJECTIVE: Eosinophilic esophagitis (EoE) is a chronic esophageal inflammatory condition with a paucity of information on health-related quality of life (HRQOL). The objective of the study was to report on the measurement properties of the PedsQL EoE Module. METHODS: The PedsQL EoE Module was completed in a multisite study by 196 pediatric patients with EoE and 262 parents of patients with EoE. RESULTS: The PedsQL EoE Module scales evidenced excellent feasibility (0.6%-3.1% missing), excellent group comparison reliability across total scale scores (patient α 0.93; parent proxy α 0.94), good reliability for the 7 individual scales (patient α 0.75-0.87; parent proxy α 0.81-0.92), excellent test-retest reliability (patient intraclass correlation coefficient 0.88; parent intraclass correlation coefficient 0.82), demonstrated no floor effects and low ceiling effects, and demonstrated a high percentage of scaling success for most scales. Intercorrelations with the PedsQL Generic Core Scales were in the medium (0.30) to large (0.50) range. PedsQL EoE Module scores were worse among patients with active histologic disease (≥ 5 eos/hpf) compared with those in remission (patient self-report: 63.3 vs 69.9 [P < 0.05]; parent proxy report: 65.1 vs 72.3 [P < 0.01]), and those treated with dietary restrictions compared with those with no restrictions (patient self-report: 61.6 vs 74.3 [P < 0.01]; parent proxy report: 65.5 vs 74.7 [P < 0.01]). CONCLUSIONS: The results demonstrate excellent measurement properties of the PedsQL EoE Module. Patients with active histologic disease and those treated with dietary restrictions demonstrated worse PedsQL scores. The PedsQL EoE Module may be used in the evaluation of pediatric EoE disease-specific HRQOL in clinical research and practice.

Development of the Pediatric Quality of Life Inventory™ Eosinophilic Esophagitis module items: qualitative methods.

BACKGROUND: Currently there is no disease-specific outcome measure to assess the health-related quality of life (HRQOL) of pediatric patients with Eosinophilic Esophagitis (EoE). Therefore, the objective of this qualitative study was to further develop and finalize the items and support the content validity for the new Pediatric Quality of Life Inventory™ (PedsQL™) Eosinophilic Esophagitis Module. METHODS: Multiphase qualitative methodology was utilized in the development of the PedsQL™ EoE Module conceptual model. Focus interview transcripts of pediatric patients with EoE and their parents and expert review were previously used to develop the initial items and domains for the PedsQL™ EoE Module. In the current investigation, utilizing the respondent debriefing methodology, cognitive interviewing was conducted individually with pediatric patients with EoE and their parents on each newly developed item. RESULTS: Information from a total of 86 participants was obtained in combination from the previous investigation and the current study. From the previous 42 focus interviews, items were developed around the domain themes of symptoms, difficulties with eating food, treatment adherence, worry about symptoms and illness, feelings of being different than family and peers, and problems discussing EoE with others. In the current study's cognitive interviewing phase, a separate cohort of 44 participants systematically reviewed and provided feedback on each item. Items were added, modified or deleted based on this feedback. Items were finalized after this feedback from patients and parents. CONCLUSIONS: Using well-established qualitative methods, the content validity of the new PedsQL™ Eosinophilic Esophagitis Module items was supported in the current investigation. In the next iterative instrument development phase, the PedsQL™ Eosinophilic Esophagitis Module is now undergoing multisite national field testing.

Development of a validated patient-reported symptom metric for pediatric eosinophilic esophagitis: qualitative methods.

BACKGROUND: Previous attempts to measure symptoms in pediatric Eosinophilic Esophagitis (EoE) have not fully included patients and parents in the item development process. We sought to identify and validate key patient self-reported and parent proxy-reported outcomes (PROs) specific to EoE. METHODS: We developed methodology for focus and cognitive interviews based on the Food and Drug Administration (FDA) guidelines for PROs, the validated generic PedsQL™ guidelines, and the consolidated criteria for reporting qualitative research (COREQ). Both child (ages 8-12 and 13-18) and parent-proxy (ages 2-4, 5-7, 8-12, and 13-18) interviews were conducted. RESULTS: We conducted 75 interviews to construct the new instrument. Items were identified and developed from individual focus interviews, followed by cognitive interviews for face and content validation. Initial domains of symptom frequency and severity were developed, and open-ended questions were used to generate specific items during the focus interviews. Once developed, the instrument construct, instructions, timeframe, scoring, and specific items were systematically reviewed with a separate group of patients and their parents during the cognitive interviews. CONCLUSIONS: To capture the full impact of pediatric EoE, both histologic findings and PROs need to be included as equally important outcome measures. We have developed the face and content validated Pediatric Eosinophilic Esophagitis Symptom Score (PEESS™ v2.0). The PEESS™ v2.0 metric is now undergoing multisite national field testing as the next iterative instrument development phase.

Sporadic distribution of prion-forming ability of Sup35p from yeasts and fungi.

Sup35p of Saccharomyces cerevisiae can form the [PSI+] prion, an infectious amyloid in which the protein is largely inactive. The part of Sup35p that forms the amyloid is the region normally involved in control of mRNA turnover. The formation of [PSI+] by Sup35p's from other yeasts has been interpreted to imply that the prion-forming ability of Sup35p is conserved in evolution, and thus of survival/fitness/evolutionary value to these organisms. We surveyed a larger number of yeast and fungal species by the same criteria as used previously and find that the Sup35p from many species cannot form prions. [PSI+] could be formed by the Sup35p from Candida albicans, Candida maltosa, Debaromyces hansenii, and Kluyveromyces lactis, but orders of magnitude less often than the S. cerevisiae Sup35p converts to the prion form. The Sup35s from Schizosaccharomyces pombe and Ashbya gossypii clearly do not form [PSI+]. We were also unable to detect [PSI+] formation by the Sup35ps from Aspergillus nidulans, Aspergillus fumigatus, Magnaporthe grisea, Ustilago maydis, or Cryptococcus neoformans. Each of two C. albicans SUP35 alleles can form [PSI+], but transmission from one to the other is partially blocked. These results suggest that the prion-forming ability of Sup35p is not a conserved trait, but is an occasional deleterious side effect of a protein domain conserved for another function.

International consensus for provisions of quality-driven care in childhood-onset systemic lupus erythematosus.

OBJECTIVE: To obtain international consensus around processes that support the delivery of high-quality care to patients with childhood-onset systemic lupus erythematosus (SLE) based on current recommendations and scientific evidence. METHODS: To identify process quality indicators (QIs) for the medical care of children and adolescents with childhood-onset SLE, we sent 2 Delphi questionnaires internationally to 340 physicians who treat these patients. We set consensus at 80% of completed responses. RESULTS: Two hundred ninety-seven physicians (87%) responded to the first Delphi questionnaire and 265 physicians (76%) responded to the second questionnaire. The group achieved consensus for 26 QIs addressing laboratory testing at diagnosis, health maintenance measures, diagnosis and therapy of lupus nephritis, general preventive strategies, surveillance for medication safety, counseling and evaluation of cardiovascular risk factors, as well as transition planning. Of the 26 process QIs for use in childhood-onset SLE, 11 matched those established for adults with SLE, 9 required modification, and consensus was reached for an additional 6 QIs specific to children. CONCLUSION: An international consensus for a set of process QIs for childhood-onset SLE was reached that considers unique aspects of children with childhood-onset SLE. The presented set of QIs for children and adolescents with childhood-onset SLE defines agreed-upon standards of medical care.