Classification of intestinal T-cell receptor repertoires using machine learning methods can identify patients with coeliac disease regardless of dietary gluten status.
Classification of intestinal T-cell receptor repertoires using machine learning methods can identify patients with coeliac disease regardless of dietary gluten status.
复制标题
DOI：
10.1002/path.5592
复制
发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Soilleux EJ
中科院分区：
文献类型：
--
作者：
Foers AD;Shoukat MS;Welsh OE;Donovan K;Petry R;Evans SC;FitzPatrick ME;Collins N;Klenerman P;Fowler A;Soilleux EJ
在乳糜泻(CED)中，免疫介导的小肠损伤是由面筋引起的，导致不同的症状和并发症，有时包括侵袭性T细胞淋巴瘤。诊断主要基于十二指肠活检的组织病理学检查，病理学家之间的一致性较差，如果摄入面筋不足，组织学上的微小异常就会混淆。CED的发病机制既涉及CD_4~+T细胞介导的面筋识别，也涉及CD_8~+和γδT细胞介导的炎症，先前的研究表明CED中γδT细胞群发生永久性改变。我们利用这一认识，探索了大宗T细胞受体(TCR)测序在评估CED十二指肠活检中的诊断价值。从十二指肠活检组织中提取的基因组DNA进行TcR-δ(Trd)和TcR- = (Trg)的测序。我们开发了一种基于机器学习的TCR曲目分析方法，通过诊断对样本进行分类。采用留一法交叉验证(LOOCV)对分类算法进行验证。使用TRD诊断标准，100%(22/22)的十二指肠活检被正确分类，LOOCV准确率为91%。应用TCR-γ(TRG)诊断标准，诊断正确率为94.4%(51/54)，LOOCV为87%。十二指肠活检TRG图谱分析使CED患者在严格的无面筋饮食至少6个月后对活检组织进行了准确的分类，而目前的测试可能会错误地对这些患者进行分类。这一结果反映了CED患者十二指肠γδTCR谱的永久性变化，即使在没有面筋摄入的情况下也是如此。我们的方法可以补充或取代CED的组织病理学诊断，并可能在不能耐受膳食面筋的患者的诊断测试中具有特殊的临床实用价值，以及对具有可疑特征的十二指肠活检进行评估。该方法可推广到任何TCR/BCR基因座和任何测序平台，具有在适应性免疫反应介导或调节的条件下预测诊断或预后的潜力。©2020作者。《病理学杂志》由John Wiley&Sons，Ltd.代表大不列颠和爱尔兰病理学会出版。
In coeliac disease (CeD), immune‐mediated small intestinal damage is precipitated by gluten, leading to variable symptoms and complications, occasionally including aggressive T‐cell lymphoma. Diagnosis, based primarily on histopathological examination of duodenal biopsies, is confounded by poor concordance between pathologists and minimal histological abnormality if insufficient gluten is consumed. CeD pathogenesis involves both CD4+ T‐cell‐mediated gluten recognition and CD8+ and γδ T‐cell‐mediated inflammation, with a previous study demonstrating a permanent change in γδ T‐cell populations in CeD. We leveraged this understanding and explored the diagnostic utility of bulk T‐cell receptor (TCR) sequencing in assessing duodenal biopsies in CeD. Genomic DNA extracted from duodenal biopsies underwent sequencing for TCR‐δ (TRD) (CeD, n = 11; non‐CeD, n = 11) and TCR‐γ (TRG) (CeD, n = 33; non‐CeD, n = 21). We developed a novel machine learning‐based analysis of the TCR repertoire, clustering samples by diagnosis. Leave‐one‐out cross‐validation (LOOCV) was performed to validate the classification algorithm. Using TRD repertoire, 100% (22/22) of duodenal biopsies were correctly classified, with a LOOCV accuracy of 91%. Using TCR‐γ (TRG) repertoire, 94.4% (51/54) of duodenal biopsies were correctly classified, with LOOCV of 87%. Duodenal biopsy TRG repertoire analysis permitted accurate classification of biopsies from patients with CeD following a strict gluten‐free diet for at least 6 months, who would be misclassified by current tests. This result reflects permanent changes to the duodenal γδ TCR repertoire in CeD, even in the absence of gluten consumption. Our method could complement or replace histopathological diagnosis in CeD and might have particular clinical utility in the diagnostic testing of patients unable to tolerate dietary gluten, and for assessing duodenal biopsies with equivocal features. This approach is generalisable to any TCR/BCR locus and any sequencing platform, with potential to predict diagnosis or prognosis in conditions mediated or modulated by the adaptive immune response. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
登录
查看更多内容
影响因子：
30.8
作者：
Emerson, Ryan O.;DeWitt, William S.;Robins, Harlan S.
通讯作者：
Robins, Harlan S.
影响因子：
13.6
作者：
Freitag, T;Schulze-Koops, H;Schuppan, D
通讯作者：
Schuppan, D
影响因子：
32.4
作者：
Broughton, Sophie E.;Petersen, Jan;Rossjohn, Jamie
通讯作者：
Rossjohn, Jamie
影响因子：
3.1
作者：
Calleja, Sara;Vivas, Santiago;Ruiz de Morales, Jose G.
通讯作者：
Ruiz de Morales, Jose G.
Stard 2015：用于报告诊断准确性研究的基本项目的更新列表。
DOI：
10.1136/bmj.h5527
发表时间：
2015-10-28
期刊：
BMJ (Clinical research ed.)
影响因子：
--
作者：
Bossuyt PM;Reitsma JB;Bruns DE;Gatsonis CA;Glasziou PP;Irwig L;Lijmer JG;Moher D;Rennie D;de Vet HC;Kressel HY;Rifai N;Golub RM;Altman DG;Hooft L;Korevaar DA;Cohen JF;STARD Group
通讯作者：
STARD Group