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Original Article Research on Establishing a Core Outcome Set for Clinical Research of Traditional Chinese Medicine in Children with Abdominal Henoch-Schonlein Purpura J Tong, C Liang, H Dong, X Peng, Y Hu, J Liu, Y Zhang, Y Yang, Y Liu Abstract Objective: This study aims to investigate and analyse the outcomes reported in c and to establish the core outcome set (COS) for children with abdominal Henoch-Schonlein purpura (HSP). Methods: Following standard operating procedures for COS development, an systematic review was conducted to extract outcomes from the relevant clinical studies, then conducted two rounds of Delphi study, after that a consensus meeting was held to finalise COS. Results: A total of 6 outcomes were included in the final COS: the degree of abdominal pain, time to abdominal pain disappearance, and time to bloody stool disappearance, and the incidence of adverse reactions or complications. Conclusion: A COS comprising 6 outcomes for abdominal HSP has been established, providing a valuable reference for the selection of outcomes in future clinical trials in this area. Keyword : Children; Core outcome set; IgA vasculitis; Purpura BackgroundImmunoglobulin A vasculitis (IgAV), commonly referred to Henoch-Schonlein purpura (HSP), is a type of non-thrombocytopenic small-vessel vasculitis and is the most common form of childhood systemic vasculitis (with an annual incidence ranging from 3-26.7 per 100,000, depending on the country).1 The disease typically manifests with a palpable purpuric rash, gastrointestinal pain and bleeding,2 kidney involvement, arthralgia, and/or arthritis.3 Abdominal involvement is characterised by paroxysmal diffuse abdominal pain, often accompanied by gastrointestinal bleeding.4 When gastrointestinal symptoms are typical, it is referred to as abdominal Henoch-Schonlein purpura (AHSP). The clinical efficacy and safety evaluation of medical interventions are typically based on the measurement and analysis of specific clinical outcomes.5 However, studies have found that the outcomes used in clinical research are frequently inconsistent, nonstandard, or inessential, weakening the scientific and practical nature of research results and leading to research waste.6,7 To address the multifaceted issues related to outcomes that are reported in clinical rials, experts in evidence-based medicine and clinical research methodology have proposed strategies to establish core outcome set (COS). These sets represent an agreed-upon minimum standardised set of outcomes that should be measured assessed and reported in all trials focusing on a specific condition.8-10 The development of a core outcome set for traditional Chinese medicine in abdominal Henoch-Schonlein purpura would minimise the heterogeneity of reported results and improve the methodological quality of clinical research in Traditional Chinese Medicine (TCM), which is important for international recognition. MethodsWe followed Core Outcome Measures in Effectiveness Trials (COMET) guidelines for this COS development study and reported on it by Core Outcome Set–Standards for Reporting.11 The current report was drafted according to Core Outcome Set–Standards for Reporting guidelines, which include a systematic review, Delphi process, and consensus meeting. The production process of the core indicator set is shown in Figure 1.
Registration Experts Committee In consideration of geographical balance, experts from various regions in China were invited. The expert committee to be included is as follows:
The secretary team collected and verified questionnaires, following the research process as planned. The expert committee facilitated the Delphi survey and will ultimately develop the final core outcome set in the consensus meeting. Scope
This COS is intended to serve as a standard for all clinical research on TCM focusing on the effectiveness and safety of interventions for abdominal Henoch-Schonlein purpura. Systematic Review Inclusion criteria: (1) Research type: a clinical trial; (2) Participation: Participants were meet the diagnostic criteria of HSP (abdominal type) or HSP (cutaneous types, abdominal type) of traditional Chinese medicine and /or Western medicine; Participants were under 18 years of age;(3) Design of experimental and control groups: The intervention measures for the experimental group and the control group are traditional Chinese medicine and / or integrated traditional Chinese and Western medicine, and the form of contrast is not limited; (4) Outcome: no limit on outcome indicators and follow-up time; Exclusion criteria: (1) HSP of mixed type with abdominal gastrointestinal symptoms (ICD-10 code D69.006) and other organs and systems other than common five type were excluded; (2) The information of outcome indicators cannot be obtained. Two reviewers independently screened citations and extracted data on study characteristics, outcomes, and measures (with a third author as arbiter if needed). The frequency of occurrence of each outcome measure in each study was recorded, and the reporting rate was calculated. We only extracted the outcome indicators included in the literature report, classified all indicators according to professional knowledge without duplicate removal, and drafted the preliminary list of outcomes and outcome domains. Semi-structured Interviews The target population was selected using purposive sampling, and the sample size was determined based on "information saturation". A questionnaire survey was conducted among Chinese and Western children's HSP clinical experts/researchers, focusing on interviews with clinical experts who specialise in Chinese medicine in treating children with AHSP. Considering the varying professional titles of the interviewees and the diverse capacities of hospitals in providing medical care, education, and conducting medical research, we selected some clinicians from the departments of traditional Chinese medicine specialising in paediatrics, digestion, and dermatology. This group included directors, deputy directors, and attending doctors for the interviews. Semi-structured interviews are conducted through a combination of online voice interviews and face-to-face interviews by qualified interviewers. Based on the interview outline prepared in advance, the interviewees, through qualitative semi-structured interviews, based on professional theoretical knowledge and clinical experience, provided important outcomes regarding the clinical efficacy in AHSP clinical trials. They also shared relevant information about the measurement time points based on their professional theoretical knowledge and clinical experience. Establishing the preliminary outcome domain, lay the foundation for the design of the Delphi expert questionnaire. Delphi Study We invited experienced experts from various regions and medical institutions in China to participate in the questionnaire survey. The selection of experts is primarily based on database queries, telephone consultations, and industry recommendations. This includes abdominal HSP's clinical experts in traditional Chinese medicine and Western medicine, clinical researchers and other relevant professionals. In the end, there were four Western medicine experts, one pharmacy expert, and 31 Chinese medicine experts joined. First Round Participants would be asked to score individual outcomes using the nine-point Likert scale: 1 to 3 indicate that the outcome is not important, 4 to 6 suggest it is important but not critical, and 7 to 9 indicate that the outcome is critical. This scale was created by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) working group and has been widely adopted by developers of core outcome sets. Additionally, participants were invited to suggest any outcome measures that they would consider relevant but are missing from the list of outcomes. Any additional outcomes would be considered by the research group and included in the scoring in the second round of Delphi. When the first-round survey were completed, we collected questionnaires and conducted statistical analysis. A standardised definition will be applied to the results to identify core outcomes, as defined by the 70/15% consensus definition as advocated by the COMET initiative.13 The criteria are as follows: (1) Consensus inclusion: ≥70% of the participants scored outcomes as 7-9, and <15% of the participants scored a outcome as 1-3. (2) Consensus exclusion: If 70% or more of the participants scored outcomes as 1-3, and less than 15% rated a outcome as 7-9. (3) No consensus: Values other than the above.12 At the end of the first round of Delphi, outcomes that achieve "Consensus in" would be included in the preliminary core outcome set and discussed in the subsequent consensus meeting. There is no need to repeat scoring in the second round of Delphi. Outcomes that achieved "Consensus out" will be excluded directly and will not be displayed repeatedly in the second round of questionnaire. Outcomes that achieved "No consensus" would form the questionnaire of the second round. Second Round Consensus Meeting After the consensus meeting, the preliminary core outcome set will be further clarified into three categories: A1 (outcomes that are critical and require reporting) and A2 (conditional reporting outcome: important but may not be reported due to lack of relevance or feasibility). The remaining outcome that entered the preliminary core outcome indicator set but did not reach a consensus on inclusion would be automatically classified as A3 (outcomes that are important can be reported as an option). Experts were convened to discuss all indicators included in COS, covering their definitions, measurement methods, and significance. They also voted on the preliminary core outcome set and immediately compiled statistics on the voting results on the spot to clarify outcomes agreed upon by consensus. The consensus definition for inclusion in the COS is as follows: (1) A1 outcomes: at least 80% of respondents had to vote that the item should be included in the final COS. (2) A2 outcomes: at least 65% of respondents had to vote that the item should be included in final COS. (3) Outcomes that do not meet the above conditions are classified as A3. ResultSystematic Review
From the functional attributes of the outcomes, it is planned to categorise the preliminary outcome items by professional knowledge to seven outcome domains: Clinical symptoms and signs index, overall efficacy index, TCM syndrome-type efficacy scores, blood biochemical outcomes, safety outcomes (including adverse reactions and complications) and other outcomes. Semi-structured Interviews Delphi Study
Of the 92 preliminary outcomes presented to the Delphi panel in round 1, we found that 14 had met the criteria of consensus. Therefore, they were included in the preliminary list of core outcome set after this round. No outcomes were excluded after round one. In round two of the Delphi process, the remaining 78 outcomes were once again presented to the panelists from round one, 36 questionnaires were submitted to 36 experts who participated in the first round, 35 were returned, and the percentage of experts in favor was 97.22%. By the end of this round, an additional 4 outcomes had reached consensus. Therefore, a total of 18 outcomes were selected for the preliminary core outcome indicator set for discussion of a consensus meeting (Table 2).
During the two rounds of Delphi, a total of 17 additional outcomes were identified, including Rash (Range and degree of rash, The severity and color of the rash, Skin rash on face), Digestive system (Fasting time, Helicobacter pylori-positive, Degree of repair of digestive tract mucosa (such as gastrointestinal congestion and oedema, bleeding point, erosion, ulcer range, location, etc.)), Overall efficacy (The incidence rate of abdominal HSP, Diet recovery, Selection of hormone varieties, initial daily dose, initial use time, and hormone reduction, Glucocorticoid reduction time, Degree of malnutrition in children, The number of cases of concurrent Henoch-Schonlein purpura nephritis), Biochemical indicators (Prealbumin, transferrin, retinol, Anti-streptococcal haemolytic (ASO) concentration), Cellular immune index(Autoantibody related tests, Cell factor), Security (Liver and kidney function). These indicators were discussed together at the expert consensus meeting. Consensus Meeting
DiscussionThis study followed established COMET methods for COS development. We used systematic review methods and conducted qualitative interviews with the clinicians to compile a comprehensive list of potential outcomes. Robust consensus-building (Delphi and consensus meeting) methods were then used to establish 6 outcomes for inclusion in the final core outcome set.15 The outcomes are relevant for children and are appropriate for all cases of abdominal Henoch-Schonlein purpura. It is anticipated that the outcomes will be used in future clinical and research studies, and reviews, and for helping to develop future guidelines for abdominal Henoch-Schonlein purpura.16 In the previous systematic review, we found that the outcomes extracted from the literature were heterogeneous and numerous. Some outcomes had repetitive meanings or unclear definitions, reflecting the heterogeneity of outcomes for abdominal Henoch-Schonlein purpura. Although a common vasculitis in pediatric practice, well-designed controlled studies are lacking.17 This is partially due to the usual self-limiting nature of the disease.18,19 Therefore, the significant heterogeneity among outcomes measured and reported is a common issue across all trials.20 When outcome heterogeneity arises, it hampers the ability to compare the effectiveness of interventions across trials and to combine trial results (such as in a meta-analysis). This leads to significant inefficiencies in research and contributes to research waste, ultimately creating barriers to greater evidence-based practice. We chose an online Delphi method because it allowed for the participation of clinicians and researchers from multiple sites across different areas. This strategy also enabled the purposeful selection of a panel to ensure representation of a variety of stakeholders from different areas and healthcare systems, including both professionals and patients.20 The use of the anonymous Questionnaire Star software also helped minimise social pressures when it came to voting. This enabled the study to involve a high level of expert participation, enhancing the accuracy of the data and results while reducing bias. Since the Delphi survey was disseminated via email and an online questionnaire, it was easy to access to ascertain the total number of individuals approached and, consequently, the proportion who participated. Also, although reminders for completion were circulated, not all participants who took part in round one participated in round two.21 During the expert consensus meeting, there were varying opinions among the experts regarding individual outcomes with higher scores in the Delphi questionnaire, such as the improvement of lower intestinal wall oedema by abdominal ultrasonography. Although ultrasound is economical and easy to operate, it is a relatively subjective examination and greatly influenced by the patient's condition, ultrasound equipment, and operator. Therefore, it was included in A2 (conditional reporting outcome). We recommend that authors consider the study context and participant when interpreting this outcome. There is a need for future research to determine the best methods to operationalise these outcomes.22 In particular, relevant outcomes of traditional Chinese medicine, such as the TCM syndrome type efficacy score, can be used when conducting a clinical trial related to traditional Chinese medicine intervention. Selecting a COS is only part of the process of standardising outcomes.15 How each outcome should be defined and measured plays a fundamental role in ensuring that future pooling of data is possible.23-25 Defining these outcomes will require an initial systematic review of reported definitions, followed by a consensus process. The responses in Delphi suggested that establishing a consensus process for utilising these outcomes would be highly complex and challenging; nevertheless, the outcomes identified during the process are expected to be of interest to researchers and other stakeholders. To date, there is no consensus on the optimal method for defining and quantifying the outcome measures included in this core outcome set. Also, there is no evidence or consensus to date on what time points are the most beneficial time points for measurement. Most intervention trials do not utilise validated measurement instruments to report outcome measures.26 The next phase will be to determine how to measure the selected outcome measures in the final core outcome set by conducting a systematic review to identify the available outcome measurement instruments are available for the outcome measures included in this core outcome set.27 Methodology for developing of core outcome sets is evolving, and we acknowledge that our COS will need regular updates as new outcomes and metrics are developed over time. LimitationsThis study did not utilise a more comprehensive mixed methods approach, which would have involved conducting patient interviews alongside our systematic review, to determine outcomes for incorporation in the Delphi round of the core outcome set development process.6,26 However, this was mitigated by including them in semi-structured interviews and by extracting outcomes during the systematic review. Additionally, Delphi round one participants were enabled to suggest additional outcomes for consideration. It could be confirmed by a recent study that outcomes obtained from patient interviews do not directly influence the final core outcome set because they coincide with the outcomes presented after round one of the Delphi process.28 Besides, there is guidance that recommends maximising the response rate from a variety of groups.29 In addition, it is important to strike the right balance between the feasibility of using the COS and obtaining sufficient depth of information to distinguish between outcomes of interest. Face-to-face approaches allow for more extensive discussions but are constrained by limited due to COVID-19, resulting in a restricted number of participants in the face-to-face meetings. We found that online experts may be influenced by various factors such as region, environment, and equipment. The participation rate is generally slightly lower than that of offline experts, and they are unable to actively express their suggestions on the topic of discussion. However, through the statistics of the voting results of the consensus meeting, we believe that this limitation was significantly mitigated by the high agreement in the online panel of participants in consultation round.30 The respondents and included literature in this study were primarily based on clinical experts and trials of traditional Chinese medicine. The number of Western medicine experts is relatively small. The best approach would be to conduct interviews and Delphi processes with both Western medicine and traditional Chinese medicine practitioners. Contrasting their different COS opinions through the process so as to come up with a standard that is useful for the aim of TCM clinical trials in abdominal Henoch-Schonlein purpura. An extension of this work would be to repeat the process including a higher or more balanced proportion of participants from Western medicine participants, to determine whether the choice of outcomes changes. Future iterations of the COS are expected and encouraged to enhance its utility. Future work may specifically address some of the sampling limitations in our study (e.g., a broader range of providers and international representation) or may focus on refining the domains (e.g., evaluating applicability across different diagnoses or interventions).31 COS Applying AdviceWe believe the COS should be utilised by future trialists as the minimum set of outcomes that should be collected in an HSP trial. Importantly, this COS represents a crucial step towards enhancing and advancing much-needed evidence synthesis in this specific disease area32,33 It is challenging task to include all COS outcomes in an individual clinical trial. And the outcomes that have not been included in COS are also of great clinical significance. We need to have a more accurate understanding of the different categories in COS for abdominal HSP. The four outcomes of A1 are critical and require reporting in a clinical trial. The other two outcomes of A2 are conditional reporting outcome, and it is important but may not be reported due to lack of relevance or feasibility. Furthermore, when clinical trial focus on traditional Chinese medicine or when researchers have the conditions to perform abdominal ultrasound for intestinal wall oedema, the above outcomes are required to be reported. ConclusionIn summary, we developed a Delphi expert questionnaire by summarising relevant literature and semi-structured interview results in the early stage. Subsequently, we held an expert consensus meeting based on the Delphi questionnaire results. Through this process, we identified a total set of 6 core outcomes and recommend that these outcomes be minimally measured in clinical trail assessing abdominal Henoch-Schonlein purpura in children. It will depend on the study population, the study design, and the intervention being assessed to determine which outcomes are appropriate to include. List of consensus experts who participated in COS construction (in alphabetical order by pinyin of last name) Conflict of InterestAll authors have disclosed no conflicts of interest. References1. Davin JC, Coppo R. Henoch-Schönlein purpura nephritis in children. Nat Rev Nephrol 2014;10:563-73. 2. Peruzzi L, Coppo R. IgA vasculitis nephritis in children and adults: one or different entities? Pediatr Nephrol 2021;36:2615-25. 3. Dyga K, Szczepańska M. IgA vasculitis with nephritis in children. Adv Clin Exp Med 2020;29:513-9. 4. Penido M, Palma LMP. IgA vasculitis in children. J Bras Nefrol 2022;44:3-5. 5. Jin X, Pang B, Zhang J, et al. Core Outcome Set for Clinical Trials on Coronavirus Disease 2019 (COS-COVID). Engineering (Beijing) 2020;6:1147-52. 6. Sinha IP, Gallagher R, Williamson PR, Smyth RL. 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