Cohort profile: Multicenter Networks for Ideal Outcomes of Rare Pediatric Endocrine and Metabolic Diseases in Korea (OUTSPREAD study)
Article information
, Chong Kun Cheon2,3,*, Junghwan Suh4, Jung-Eun Moon5, Moon Bae Ahn6, Seong Hwan Chang7, Jieun Lee8, Jin Ho Choi9, Minsun Kim10,11,12, Han Hyuk Lim13,14, Jaehyun Kim15,16, Shin-Hye Kim17, Hae Sang Lee18, Yena Lee19, Eungu Kang20, Se Young Kim21, Yong Hee Hong22, Seung Yang23, Heon-Seok Han24, Sochung Chung25, Won Kyoung Cho26, Eun Young Kim27, Jin Kyung Kim28, Kye Shik Shim29, Eun-Gyong Yoo30, Hae Soon Kim31, Aram Yang32, Sejin Kim33, Hyo-Kyoung Nam34,35, Sung Yoon Cho,36, Young Ah Lee,1,16
Abstract
Rare endocrine diseases are complex conditions that require lifelong specialized care due to their chronic nature and associated long-term complications. In Korea, a lack of nationwide data on clinical practice and outcomes has limited progress in patient care. Therefore, the Multicenter Networks for Ideal Outcomes of Pediatric Rare Endocrine and Metabolic Disease (OUTSPREAD) study was initiated. This study involves 30 centers across Korea. The study aims to improve the long-term prognosis of Korean patients with rare endocrine diseases by collecting comprehensive clinical data, biospecimens, and patient-reported outcomes to identify complications and unmet needs in patient care. Patients with childhood-onset pituitary, adrenal, or gonadal disorders, such as craniopharyngioma, congenital adrenal hyperplasia (CAH), and Turner syndrome were prioritized. The planned enrollment is 1,300 patients during the first study phase (2022–2024). Clinical, biochemical, and imaging data from diagnosis, treatment, and follow-up during 1980–2023 were retrospectively reviewed. For patients who agreed to participate in the prospective cohort, clinical data and biospecimens will be prospectively collected to discover ideal biomarkers that predict the effectiveness of disease control measures and prognosis. Patient-reported outcomes, including quality of life and depression scales, will be evaluated to assess psychosocial outcomes. Additionally, a substudy on CAH patients will develop a steroid hormone profiling method using liquid chromatography-tandem mass spectrometry to improve diagnosis and monitoring of treatment outcomes. This study will address unmet clinical needs by discovering ideal biomarkers, introducing evidence-based treatment guidelines, and ultimately improving long-term outcomes in the areas of rare endocrine and metabolic diseases.
Highlights
· The OUTSPREAD study is a nationwide, multicenter initiative in Korea aimed at improving the long-term prognosis of patients with rare pediatric endocrine diseases by collecting comprehensive clinical, biochemical, and psychosocial data.
· The study prioritizes rare endocrine diseases such as craniopharyngioma, congenital adrenal hyperplasia, and Turner syndrome, aiming to enroll 1,300 patients during its initial phase (2022–2024) and collect data spanning from 1980 to 2023.
· By identifying ideal biomarkers and addressing unmet clinical needs, the study seeks to establish evidence-based guidelines and enhance the diagnosis, treatment, and quality of life for affected patients.
Introduction
Childhood-onset rare endocrine disorders affecting the pituitary, adrenal, and gonadal systems are complex conditions that necessitate lifelong specialized care. These disorders present unique challenges for pediatric patients as hormonal deficiencies frequently disrupt normal growth and pubertal progression [1-3]. Timely and appropriate hormone replacement therapy is therefore essential to ensure optimal growth and development in these patients [4,5].
Craniopharyngioma (CRP), congenital adrenal hyperplasia (CAH), and Turner syndrome (TS) are representative examples of rare endocrine disorders affecting the pituitary, adrenal, and gonadal systems. Even with proper hormone replacement therapy, patients with these conditions are at a high risk for complications, including osteoporosis, metabolic syndrome, diabetes, cardiovascular disease, and infertility [6-8]. These complications can have a profound impact on the quality of life for both the patients and their caregivers. In addition, these patients often experience significant psychosocial challenges that arise from both the burden of chronic illness and the specific psychosocial issues inherent to each disorder [9-11].
In Korea, research on childhood-onset rare endocrine disorders has been limited with most studies confined to single institutions [12-15]. Due to the rarity of these conditions, multicenter collaborations are crucial for generating meaningful research and improving patient outcomes. Globally, various initiatives have been established to address the challenges of rare endocrine disorders, including the German CRP Registry [16], I-CAH Registry [17], the InsighTS Registry [18], and the European Reference Network for Rare Endocrine Conditions [19]. However, healthcare environments differ across countries necessitating research and guidelines tailored to local contexts. To date, there has not been a multicenter cohort study focused on rare endocrine disorders in Korea.
The Multicenter Networks for Ideal Outcomes of Rare Pediatric Endocrine and Metabolic Disease (OUTSPREAD) study is the first nationwide Korean multicenter cohort study focusing on rare pediatric endocrine disorders. The study aims to improve the long-term prognosis of patients by collecting comprehensive clinical data to identify complications and unmet needs. In addition, the study seeks to analyze biospecimens to discover novel biomarkers for disease management. Ultimately, the study's goal is to propose optimal hormone therapy regimens and develop clinical guidelines, thereby contributing to improved patient care and outcomes.
Study population and recruitment
Patients with childhood-onset endocrine disorders affecting the pituitary, adrenal, or gonadal systems were prioritized in this study. Individuals diagnosed with these conditions after 1980 and before the age of 18 years or those under the care of pediatric endocrinology departments were included. These patients were from 30 hospitals across Korea. The study was initially started at 16 hospitals in 2022 and was expanded to include 30 hospitals as of 2024. These participating hospitals are distributed across various regions of the country, including Seoul, Incheon, Gyeonggi, Chungcheong, Gyeongsang, and Jeolla, ensuring broad geographic representation for the study (Fig. 1).
Geographic distribution of participating hospitals. SNU, Seoul National University Children’s Hospital; KHU, Kyung Hee University Hospital; SMC, Samsung Medical Center; CMC, Seoul St. Mary's Hospital; SEV, Severance Hospital; AMC, Asan Medical Center Children's Hospital; KBH, Kangbuk Samsung Hospital; KUH, Konkuk University Medical Center; KUG, Korea University Guro Hospital; SGP, Sanggye Paik Hospital; EMC, Ewha Womans University Medical Center; HYS, Hanyang University Seoul Hospital; KUM, Korea University Ansan Hospital; SUB, Seoul National University Bundang Hospital; AJU, Ajou University Hospital; HMC, Hallym University Sacred Heart Hospital; DMC, Bundang Jesaeng General Hospital; CHA, CHA Bundang Medical Center; SVT, St. Vincent’s Hospital; SCH, Soonchunhyang University Bucheon Hospital; HYG, Hanyang University Guri Hospital; IUH, Inha University Hospital; CNU, Chungnam National University Hospital; CBU, Chungbuk National University Hospital; JBU, Jeonbuk National University Hospital; JNU, Chonnam National University Hospital; CSU, Chosun University Hospital; KNU, Kyungpook National University Chilgok Hospital; DCU, Daegu Catholic University Medical Center; KMU, Kyemyung University Dongsan Hospital; PNU, Pusan National University Children's Hospital.
The goal for 2022 to 2024 is to enroll a total of 1,300 participants spanning the three primary conditions: 250 patients with CRP, 350 with CAH, and 700 with TS. The inclusion criteria for each disease group are these. CRP patients with a confirmed pathological diagnosis following brain tumor surgery are included [6]. CAH patients diagnosed based on clinical presentation, biochemical tests, or genetic analysis [7] are also included. TS patients are included if presenting with a female phenotype and having an X chromosome deletion confirmed by chromosomal analysis [8].
Cohort design and follow-up protocol
The cohort comprises two components: a retrospective cohort and a prospective cohort (Fig. 2). For the retrospective cohort, we conducted a comprehensive review of medical records spanning from 1980 to 2023, encompassing the period from initial diagnosis through each treatment course to the most recent follow-up. We identified specific time points for data collection from medical records for each disorder. These are detailed in Table 1. These time points are applicable to both the retrospective and prospective cohorts and ensure consistency in data collection across the study. Patients who provided informed consent for ongoing research participation are enrolled in the prospective cohort. These participants will undergo annual follow-up evaluations until 2032, allowing for an extended observation period of disease progression and treatment outcomes.
Study design. F/U, follow-up.
Key time points for clinical data collection by disease categories
Clinical data collection
Clinical information collected included demographic information, birth history, family history, anthropometrics, karyotype or genotypes, disease course, hormone replacement therapy, other medical treatments, or surgical interventions. For anthropometric data, z-scores were calculated based on the 2017 Korean National Growth Charts [20]. Biochemical data, including hormone levels, both basal and stimulated, and fasting metabolic profiles, were reviewed. Imaging studies, including bone age assessment and magnetic resonance imaging, computed tomography, and ultrasonography findings for brain, thyroid, cardiac, abdominal, and gonadal evaluations, were also analyzed. Detailed measurements for this cohort are presented in Table 2.
Multidimensional assessment parameters in the cohort study
Questionnaires
Annual questionnaires assessing psychosocial factors, medical history, and family history are collected from participants in the prospective cohort study (Table 2). Psychosocial outcomes are measured using validated instruments, including the PedsQL 4.0 for quality of life [21] and age-appropriate depression scales (Korean version of the Children's Depression Inventory or Beck's Depression Inventory) [22,23]. Caregiver quality of life is evaluated using the CarerQoL-7D Korean version [24], and stress levels are measured using the Perceived Stress Scale-14 [25]. The questionnaires also collect information on participants' menstrual and psychosocial disease history and family histories of chronic conditions including diabetes, dyslipidemia, cardiovascular diseases, and thyroid disorders.
Biological sample collection
For participants in the prospective cohort, blood, urine, saliva, and stool samples are collected annually alongside clinical data (Table 2). Participants are instructed to collect urine, saliva, and stool samples on the same day as blood sampling. These specimens will be used to identify potential biomarkers predictive of disease control and prognosis.
Substudy: Development of steroid hormone profiling for CAH diagnosis and monitoring
As part of this cohort study, we have been developing a comprehensive steroid hormone profiling method using liquid chromatography-tandem mass spectrometry. This approach addresses two critical needs in the management of CAH: (1) improving the differential diagnosis of various CAH types, particularly enzyme deficiencies beyond 21-hydroxylase deficiency (21OHD); and (2) enhancing the monitoring of 21OHD treatment. Annually collected biospecimens from patients with CAH will be used to validate the newly developed steroid hormone profiling method.
Conclusion
The OUTSPREAD cohort, the first nationwide study in Korea focusing on rare endocrine disorders, seeks to address the unmet needs of patients from childhood through adulthood. By collecting comprehensive clinical data and fostering collaboration across a national research network, this study aims to develop optimal management guidelines for rare pediatric endocrine diseases, potentially reducing long-term complications and enhancing patients' quality of life. The extensive biospecimen collection serves as a valuable resource for future biomarker research. This could lead to the discovery of novel diagnostic and prognostic indicators. Additionally, this research will provide for evidence-based policy reforms and facilitate the development of novel therapeutic approaches that ultimately enhance patient care and healthcare efficiency in the management of rare pediatric endocrine disorders.
Notes
Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Funding
This research was supported and funded by SNUH Lee Kun-Hee Child Cancer & Rare Disease Project, Republic of Korea (grant number: 22C-007-0000).
Author Contribution
Conceptualization: YJL, CKC, JS, JM, MBA, JL, JHC, MK, HHL, JK, SK, HSL, YL, EK, SYK, YH H, SY, HH, SC, WKC, EYK, JKK, KSS, EY, HSK, AY, SK, HN, SYC, YAL; Data curation: MBA, SHC, JL, MK, HHL, JK, HSL, YL, EK, SYK, HSK, AY, SK; Formal analysis: YJL; Funding acquisition: YAL; Methodology: CKC JS, JM, SHC, JHC, JK, SK, YHH, SY, HH, SC WKC, EYK, JKK, KSS, EY, HN, SYC; Project administration: YAL; Visualization: YJL; Writing - original draft: YJL; Writing - review & editing: YJL, CKC, JS, JM, MBA, SHC, JL, JHC, MK, HHL, JK, SK, HSL, YL, EK, SYK, YH H, SY, HH, WKC, EYK, JKK, KSS, EY, HSK, AY, SK, HN, SYC, YAL