Although this Delphi process resulted in high agreement for the diagnostic criteria, there are several limitations. In the absence of an appropriate reference standard test, or adequate data on the accuracy of clinical criteria, this process is reliant on expert opinion, which may not correlate with diagnostic accuracy. Therefore, an important next step is the validation of the criteria in a range of settings, including different geographic regions, areas of differing prevalence, and where other important differential diagnoses may be prevalent.
Application of the criteria, summarized in Box 1, requires reference to the evidence-based explanatory notes and definitions that are being prepared in parallel. These notes will clearly define and explain each feature and subcategory of the criteria and will include recommended techniques for examination, microscopy and visualization, as well as details of important differential diagnoses. To enable use of the criteria for epidemiological mapping, a training methodology will be required for non-expert health workers, similar to that developed for trachoma graders [17].
Strong consensus has been established for criteria to diagnose scabies in a variety of settings. These criteria will facilitate diagnosis and comparison of findings across studies. The 2018 criteria require validation in a range of epidemiological settings.
Panellists agreed that the most beneficial time to start CTX treatment is from birth, following a positive newborn screening test. Initiating treatment upon CTX diagnosis (with or without symptom onset) was agreed to be the next most beneficial option, followed by starting treatment upon symptom onset in diagnosed patients.
In paediatric patients, chronic diarrhoea, bilateral juvenile cataracts and intellectual disability (e.g. learning difficulties) were identified as key symptoms, supported by available literature [3, 9]. For patients who are not diagnosed until adulthood, additional symptoms include tendon xanthomas, psychiatric and neurological symptoms. Presence of these signs should prompt clinicians to refer patients for further testing, and greater awareness of these typical symptoms may aid early diagnosis and treatment [3]. Whilst some signs asked about in these questions did not reach consensus, in some instances their presentation should still prompt further investigation. As clinicians may only see a small subset of patients, whose symptoms will likely vary from patients seen by other physicians due to the heterogenous nature of CTX, this may indicate why consensus was not achieved for these questions. For example, neonatal cholestatic jaundice can often be self-limiting [39, 40], and so the proportion of patients presenting to each expert with this symptom could vary, dependant on the age of patients at presentation. Nevertheless, when prolonged and without a specific diagnosis, neonatal jaundice should raise suspicion towards a CTX diagnosis given it can potentially cause irreversible liver damage if left untreated [8, 41].
Presence of biallelic CYP27A1 pathogenic variants was considered to be the indicator of greatest diagnostic value. This suggests that, whilst the presence of key symptoms may prompt further investigation [3], molecular analysis of the CYP27A1 gene should be considered the primary means for diagnosis, with whole exome sequencing showing great promise for increasing accurate diagnoses [42]. Results indicate that patients always have elevated serum cholestanol levels and that this should be considered an appropriate secondary means for investigating a diagnosis. However, the fact that in some atypical cases patients exhibit normal cholestanol levels [43], should be acknowledged. Furthermore, raised serum cholestanol levels have been described on occasion in patients with primary biliary cirrhosis and Niemann Pick type C, and very rarely in progressive familial intrahepatic cholestasis type 3 [44]. The fact that elevated cholestanol levels are sometimes observed in other conditions should therefore be recognised when considering this indicator in the investigation of a CTX diagnosis.
A textual data set was used to capture complex implicit and explicit ideas and phrasing formulated by the delphi question. This body of text was then analysed using thematic analysis to identify and describe the derived themes. This formed the recommendations for the development of the expert derived clinical assessment protocol.
Based on the findings from this study, any proposed future research on the diagnosis of forefoot neuroma should consider validating the recommendations in supporting clinical decision-making in clinical practice. Also, there is a need to develop and test a diagnostic scoring system based on the identified recommendations from this study to diagnose forefoot neuroma.
Full-text publications were searched for best practice evidence to be used in clinical guideline development. Relevant information was collected from included studies regarding best practices on how to screen, diagnose, treat, and perform physical examinations on patients presenting with rotator cuff pathology. Publications were also searched for best practice diagnostic guidelines for imaging. Information was extracted and used to develop consensus statements. Statements were compiled into a Microsoft Excel (2007) spreadsheet. Each statement was assigned the highest level of evidence available based on the systematic review of the literature to categorize the quality of each statement, and to aid in clinical decision-making. Levels of evidence were adapted from Wright et al. [33] and ranged from randomized controlled trials (Level 1) to expert opinion (Level 5) (Table 1). Members of the core group reviewed the Excel spreadsheet, and subsequently met as a group to discuss discrepancies and finalize a draft consensus document.
For the development of screening and diagnostic statements, information was compiled from studies that proposed history-taking questions that could be used to identify or differentially diagnose rotator cuff pathology. For the development of statements pertaining to physical examination of patients presenting with rotator cuff symptoms, information was compiled from studies that discussed the use of observation, range of motion, special tests, and palpation in examination procedures. For the development of statements pertaining to investigations, information was retrieved pertaining to best practice diagnostic imaging guidelines for patients presenting with rotator cuff pathology symptoms. For statements pertaining to treatment of rotator cuff pathology, the following information was compiled: indications for non-operative management; indications for surgical management; benchmarks to treatment; and best practices with respect to exercise programs. Evidence from included publications generated 123 statements (i.e., clinical practice guidelines) for patients presenting with rotator cuff pathology. Evidence from pre-existing guidelines identified by the literature search was also cross-referenced during the development of consensus statements to ensure that the highest level of evidence was achieved. The 123 statements were circulated to all members of the expert panel for round 1 voting.
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