National Institute for Health and Care Research Applied Research Collaboration West, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.
Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
Health Technol Assess. 2022 Oct;26(44):1-310. doi: 10.3310/ZUCE8371.
Coeliac disease is an autoimmune disorder triggered by ingesting gluten. It affects approximately 1% of the UK population, but only one in three people is thought to have a diagnosis. Untreated coeliac disease may lead to malnutrition, anaemia, osteoporosis and lymphoma.
The objectives were to define at-risk groups and determine the cost-effectiveness of active case-finding strategies in primary care.
(1) Systematic review of the accuracy of potential diagnostic indicators for coeliac disease. (2) Routine data analysis to develop prediction models for identification of people who may benefit from testing for coeliac disease. (3) Systematic review of the accuracy of diagnostic tests for coeliac disease. (4) Systematic review of the accuracy of genetic tests for coeliac disease (literature search conducted in April 2021). (5) Online survey to identify diagnostic thresholds for testing, starting treatment and referral for biopsy. (6) Economic modelling to identify the cost-effectiveness of different active case-finding strategies, informed by the findings from previous objectives.
For the first systematic review, the following databases were searched from 1997 to April 2021: MEDLINE (National Library of Medicine, Bethesda, MD, USA), Embase (Elsevier, Amsterdam, the Netherlands), Cochrane Library, Web of Science™ (Clarivate™, Philadelphia, PA, USA), the World Health Organization International Clinical Trials Registry Platform ( WHO ICTRP ) and the National Institutes of Health Clinical Trials database. For the second systematic review, the following databases were searched from January 1990 to August 2020: MEDLINE, Embase, Cochrane Library, Web of Science, Kleijnen Systematic Reviews ( KSR ) Evidence, WHO ICTRP and the National Institutes of Health Clinical Trials database. For prediction model development, Clinical Practice Research Datalink GOLD, Clinical Practice Research Datalink Aurum and a subcohort of the Avon Longitudinal Study of Parents and Children were used; for estimates for the economic models, Clinical Practice Research Datalink Aurum was used.
For review 1, cohort and case-control studies reporting on a diagnostic indicator in a population with and a population without coeliac disease were eligible. For review 2, diagnostic cohort studies including patients presenting with coeliac disease symptoms who were tested with serological tests for coeliac disease and underwent a duodenal biopsy as reference standard were eligible. In both reviews, risk of bias was assessed using the quality assessment of diagnostic accuracy studies 2 tool. Bivariate random-effects meta-analyses were fitted, in which binomial likelihoods for the numbers of true positives and true negatives were assumed.
People with dermatitis herpetiformis, a family history of coeliac disease, migraine, anaemia, type 1 diabetes, osteoporosis or chronic liver disease are 1.5-2 times more likely than the general population to have coeliac disease; individual gastrointestinal symptoms were not useful for identifying coeliac disease. For children, women and men, prediction models included 24, 24 and 21 indicators of coeliac disease, respectively. The models showed good discrimination between patients with and patients without coeliac disease, but performed less well when externally validated. Serological tests were found to have good diagnostic accuracy for coeliac disease. Immunoglobulin A tissue transglutaminase had the highest sensitivity and endomysial antibody the highest specificity. There was little improvement when tests were used in combination. Survey respondents ( = 472) wanted to be 66% certain of the diagnosis from a blood test before starting a gluten-free diet if symptomatic, and 90% certain if asymptomatic. Cost-effectiveness analyses found that, among adults, and using serological testing alone, immunoglobulin A tissue transglutaminase was most cost-effective at a 1% pre-test probability (equivalent to population screening). Strategies using immunoglobulin A endomysial antibody plus human leucocyte antigen or human leucocyte antigen plus immunoglobulin A tissue transglutaminase with any pre-test probability had similar cost-effectiveness results, which were also similar to the cost-effectiveness results of immunoglobulin A tissue transglutaminase at a 1% pre-test probability. The most practical alternative for implementation within the NHS is likely to be a combination of human leucocyte antigen and immunoglobulin A tissue transglutaminase testing among those with a pre-test probability above 1.5%. Among children, the most cost-effective strategy was a 10% pre-test probability with human leucocyte antigen plus immunoglobulin A tissue transglutaminase, but there was uncertainty around the most cost-effective pre-test probability. There was substantial uncertainty in economic model results, which means that there would be great value in conducting further research.
The interpretation of meta-analyses was limited by the substantial heterogeneity between the included studies, and most included studies were judged to be at high risk of bias. The main limitations of the prediction models were that we were restricted to diagnostic indicators that were recorded by general practitioners and that, because coeliac disease is underdiagnosed, it is also under-reported in health-care data. The cost-effectiveness model is a simplification of coeliac disease and modelled an average cohort rather than individuals. Evidence was weak on the probability of routine coeliac disease diagnosis, the accuracy of serological and genetic tests and the utility of a gluten-free diet.
Population screening with immunoglobulin A tissue transglutaminase (1% pre-test probability) and of immunoglobulin A endomysial antibody followed by human leucocyte antigen testing or human leucocyte antigen testing followed by immunoglobulin A tissue transglutaminase with any pre-test probability appear to have similar cost-effectiveness results. As decisions to implement population screening cannot be made based on our economic analysis alone, and given the practical challenges of identifying patients with higher pre-test probabilities, we recommend that human leucocyte antigen combined with immunoglobulin A tissue transglutaminase testing should be considered for adults with at least a 1.5% pre-test probability of coeliac disease, equivalent to having at least one predictor. A more targeted strategy of 10% pre-test probability is recommended for children (e.g. children with anaemia).
Future work should consider whether or not population-based screening for coeliac disease could meet the UK National Screening Committee criteria and whether or not it necessitates a long-term randomised controlled trial of screening strategies. Large prospective cohort studies in which all participants receive accurate tests for coeliac disease are needed.
This study is registered as PROSPERO CRD42019115506 and CRD42020170766.
This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in ; Vol. 26, No. 44. See the NIHR Journals Library website for further project information.
乳糜泻是一种由摄入麸质引起的自身免疫性疾病。它影响了大约 1%的英国人口，但据认为只有三分之一的人得到了诊断。未经治疗的乳糜泻可能导致营养不良、贫血、骨质疏松症和淋巴瘤。
目的是确定高危人群，并确定初级保健中主动病例发现策略的成本效益。
（1）对乳糜泻潜在诊断指标的准确性进行系统评价。（2）对识别可能受益于乳糜泻检测的人群的预测模型进行常规数据分析。（3）对乳糜泻诊断试验的准确性进行系统评价。（4）对乳糜泻的遗传检测准确性进行系统评价（文献检索于 2021 年 4 月进行）。（5）通过在线调查确定检测、开始治疗和进行活检的诊断阈值。（6）根据前几项研究的结果，确定不同主动病例发现策略的成本效益。
对于第一个系统评价，从 1997 年到 2021 年 4 月，在以下数据库中进行了搜索：MEDLINE（美国国立卫生研究院，贝塞斯达，马里兰州）、Embase（爱思唯尔，阿姆斯特丹，荷兰）、Cochrane 图书馆、Web of ScienceTM（ClarivateTM，费城，宾夕法尼亚州）、世界卫生组织国际临床试验注册平台（WHO ICTRP）和美国国立卫生研究院临床试验数据库。对于第二个系统评价，从 1990 年 1 月至 2020 年 8 月，在以下数据库中进行了搜索：MEDLINE、Embase、Cochrane 图书馆、Web of Science、Kleijnen 系统评价（KSR）证据、WHO ICTRP 和美国国立卫生研究院临床试验数据库。预测模型的开发使用了临床实践研究数据链接 GOLD、临床实践研究数据链接 Aurum 和父母和孩子的阿冯纵向研究的一个子队列；经济模型的估计使用了临床实践研究数据链接 Aurum。
对于综述 1，纳入了在乳糜泻人群和非乳糜泻人群中报告诊断指标的队列和病例对照研究。对于综述 2，纳入了以乳糜泻症状就诊并接受乳糜泻血清学检测和十二指肠活检作为参考标准的诊断性队列研究。在这两项综述中，使用质量评估诊断准确性研究 2 工具评估了偏倚风险。拟合了二项式似然比的随机效应荟萃分析，其中假设二项式可能性用于真阳性和真阴性的数量。
患有疱疹样皮炎、乳糜泻家族史、偏头痛、贫血、1 型糖尿病、骨质疏松症或慢性肝病的人患乳糜泻的可能性是一般人群的 1.5-2 倍；个别胃肠道症状对识别乳糜泻没有用处。对于儿童、女性和男性，预测模型分别包括 24、24 和 21 个乳糜泻指标。这些模型在区分患有和未患有乳糜泻的患者方面表现良好，但在外部验证时表现不佳。血清学检测对乳糜泻具有良好的诊断准确性。免疫球蛋白 A 组织转谷氨酰胺酶的敏感性最高，内肌膜抗体的特异性最高。当联合使用时，并没有改善。调查受访者（n=472）希望在有症状时，通过血液检查有 66%的把握可以确诊，而在无症状时，有 90%的把握可以确诊。成本效益分析发现，在成年人中，单独使用血清学检测时，免疫球蛋白 A 组织转谷氨酰胺酶在 1%的术前概率（相当于人群筛查）时最具成本效益。使用免疫球蛋白 A 内肌膜抗体加人类白细胞抗原或人类白细胞抗原加免疫球蛋白 A 组织转谷氨酰胺酶的策略，无论术前概率如何，其成本效益结果均相似，与 1%术前概率时免疫球蛋白 A 组织转谷氨酰胺酶的成本效益结果相似。在国民保健制度（NHS）中实施的最实用的替代方案可能是在术前概率高于 1.5%的人群中结合人类白细胞抗原和免疫球蛋白 A 组织转谷氨酰胺酶检测。在儿童中，最具成本效益的策略是术前概率为 10%，使用人类白细胞抗原加免疫球蛋白 A 组织转谷氨酰胺酶，但术前概率的最具成本效益存在不确定性。经济模型结果存在很大的不确定性，这意味着进一步开展研究将具有巨大的价值。
荟萃分析的解释受到纳入研究之间存在的实质性异质性的限制，并且大多数纳入的研究被认为存在较高的偏倚风险。预测模型的主要局限性在于，我们仅限于记录在全科医生病历中的诊断指标，并且由于乳糜泻诊断不足，因此在医疗保健数据中也报告不足。成本效益模型是对乳糜泻的简化，并且对平均队列而不是个体进行建模。有关乳糜泻常规诊断的概率、血清学和遗传学检测的准确性以及无麸质饮食的实用性的证据薄弱。
在乳糜泻免疫球蛋白 A 组织转谷氨酰胺酶（1%术前概率）和免疫球蛋白 A 内肌膜抗体后进行人类白细胞抗原检测或人类白细胞抗原检测后进行免疫球蛋白 A 组织转谷氨酰胺酶检测的人群筛查似乎具有相似的成本效益结果。由于不能仅根据我们的经济分析来决定是否实施人群筛查，并且鉴于识别具有较高术前概率的患者存在实际挑战，因此我们建议对于术前概率至少为 1.5%的乳糜泻患者（即至少有一个预测因子），应考虑人类白细胞抗原联合免疫球蛋白 A 组织转谷氨酰胺酶检测。对于儿童（例如贫血儿童），建议采用 10%的术前概率更有针对性的策略。
未来的工作应考虑基于人群的乳糜泻筛查是否符合英国国家筛查委员会的标准，以及是否需要针对筛查策略的长期随机对照试验。需要进行所有参与者都接受乳糜泻准确检测的大型前瞻性队列研究。
本研究已在 PROSPERO CRD42019115506 和 CRD42020170766 中注册，并将在；第 26 卷，第 44 期。有关该项目的进一步信息，请访问 NIHR 期刊库网站。
该项目由英国国家卫生与保健研究所（NIHR）卫生技术评估计划资助，将全文发表在；第 26 卷，第 44 期。请在 NIHR 期刊库网站上查看该计划的更多项目信息。
