Data_Sheet_1_A Study Protocol for Validation and Implementation of Whole-Genome and -Transcriptome Sequencing as a Comprehensive Precision Diagnostic Test in Acute Leukemias.docx

BackgroundWhole-genome sequencing (WGS) and whole-transcriptome sequencing (WTS), with the ability to provide comprehensive genomic information, have become the focal point of research interest as novel techniques that can support precision diagnostics in routine clinical care of patients with various cancer types, including hematological malignancies. This national multi-center study, led by Genomic Medicine Sweden, aims to evaluate whether combined application of WGS and WTS (WGTS) is technically feasible and can be implemented as an efficient diagnostic tool in patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). In addition to clinical impact assessment, a health-economic evaluation of such strategy will be performed.
Methods and AnalysisThe study comprises four phases (i.e., retrospective, prospective, real-time validation, and follow-up) including approximately 700 adult and pediatric Swedish AML and ALL patients. Results of WGS for tumor (90×) and normal/germline (30×) samples as well as WTS for tumors only will be compared to current standard of care diagnostics. Primary study endpoints are diagnostic efficiency and improved diagnostic yield. Secondary endpoints are technical and clinical feasibility for routine implementation, clinical utility, and health-economic impact.
DiscussionData from this national multi-center study will be used to evaluate clinical performance of the integrated WGTS diagnostic workflow compared with standard of care. The study will also elucidate clinical and health-economic impacts of a combined WGTS strategy when implemented in routine clinical care.
Clinical Trial Registration[https://doi.org/10.1186/ISRCTN66987142], identifier [ISRCTN66987142].

【背景】全基因组测序（Whole-genome sequencing, WGS）与全转录组测序（Whole-transcriptome sequencing, WTS）可提供全面的基因组信息，作为能够支持多种癌症（包括血液系统恶性肿瘤）患者常规临床诊疗中精准诊断的新兴技术，已成为当前研究热点。本项由瑞典基因组医学（Genomic Medicine Sweden）牵头的全国多中心研究，旨在评估全基因组测序与全转录组联合检测（WGTS）在急性淋巴细胞白血病（acute lymphoblastic leukemia, ALL）及急性髓系白血病（acute myeloid leukemia, AML）患者中的技术可行性，以及其能否作为高效诊断工具应用于临床。除临床疗效评估外，本研究还将对该检测策略开展卫生经济学评价。

【方法与分析】本研究分为四个阶段，即回顾性研究、前瞻性研究、实时验证及随访研究，纳入约700名瑞典籍成人及儿童急性髓系白血病与急性淋巴细胞白血病患者。本研究将对肿瘤样本（测序深度90×）与正常/生殖系样本（测序深度30×）的全基因组测序结果，以及仅针对肿瘤样本的全转录组测序结果，与当前临床标准诊疗检测结果进行对比。本研究的主要终点为诊断效能与诊断检出率的提升；次要终点包括常规临床应用的技术与临床可行性、临床实用性及卫生经济学影响。

【讨论】本项全国多中心研究的数据，将用于评估整合式全基因组与全转录组联合检测诊断流程相较于临床标准诊疗的临床表现。本研究还将阐明全基因组与全转录组联合检测策略应用于常规临床诊疗后所产生的临床与卫生经济学影响。

【临床试验注册】DOI：10.1186/ISRCTN66987142，试验识别编号：ISRCTN66987142。