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染色体臂 1p 和 19q 缺失的检测在胶质瘤患者中的诊断准确性和成本效益。

Diagnostic test accuracy and cost-effectiveness of tests for codeletion of chromosomal arms 1p and 19q in people with glioma.

机构信息

Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK.

出版信息

Cochrane Database Syst Rev. 2022 Mar 2;3(3):CD013387. doi: 10.1002/14651858.CD013387.pub2.


DOI:10.1002/14651858.CD013387.pub2
PMID:35233774
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8889390/
Abstract

BACKGROUND: Complete deletion of both the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q), known as 1p/19q codeletion, is a mutation that can occur in gliomas. It occurs in a type of glioma known as oligodendroglioma and its higher grade counterpart known as anaplastic oligodendroglioma. Detection of 1p/19q codeletion in gliomas is important because, together with another mutation in an enzyme known as isocitrate dehydrogenase, it is needed to make the diagnosis of an oligodendroglioma. Presence of 1p/19q codeletion also informs patient prognosis and prediction of the best drug treatment. The main two tests in use are fluorescent in situ hybridisation (FISH) and polymerase chain reaction (PCR)-based loss of heterozygosity (LOH) assays (also known as PCR-based short tandem repeat or microsatellite analysis). Many other tests are available. None of the tests is perfect, although PCR-based LOH is expected to have very high sensitivity. OBJECTIVES: To estimate the sensitivity and specificity and cost-effectiveness of different deoxyribonucleic acid (DNA)-based techniques for determining 1p/19q codeletion status in glioma. SEARCH METHODS: We searched MEDLINE, Embase and BIOSIS up to July 2019. There were no restrictions based on language or date of publication. We sought economic evaluation studies from the results of this search and using the National Health Service Economic Evaluation Database. SELECTION CRITERIA: We included cross-sectional studies in adults with glioma or any subtype of glioma, presenting raw data or cross-tabulations of two or more DNA-based tests for 1p/19q codeletion. We also sought economic evaluations of these tests. DATA COLLECTION AND ANALYSIS: We followed procedures outlined in the Cochrane Handbook for Diagnostic Test Accuracy Reviews. Two review authors independently screened titles/abstracts/full texts, performed data extraction, and undertook applicability and risk of bias assessments using QUADAS-2. Meta-analyses used the hierarchical summary ROC model to estimate and compare test accuracy. We used FISH and PCR-based LOH as alternate reference standards to examine how tests compared with those in common use, and conducted a latent class analysis comparing FISH and PCR-based LOH. We constructed an economic model to evaluate cost-effectiveness. MAIN RESULTS: We included 53 studies examining: PCR-based LOH, FISH, single nucleotide polymorphism (SNP) array, next-generation sequencing (NGS), comparative genomic hybridisation (CGH), array comparative genomic hybridisation (aCGH), multiplex-ligation-dependent probe amplification (MLPA), real-time PCR, chromogenic in situ hybridisation (CISH), mass spectrometry (MS), restriction fragment length polymorphism (RFLP) analysis, G-banding, methylation array and NanoString. Risk of bias was low for only one study; most gave us concerns about how patients were selected or about missing data. We had applicability concerns about many of the studies because only patients with specific subtypes of glioma were included. 1520 participants contributed to analyses using FISH as the reference, 1304 participants to analyses involving PCR-based LOH as the reference and 262 participants to analyses of comparisons between methods from studies not including FISH or PCR-based LOH. Most evidence was available for comparison of FISH with PCR-based LOH (15 studies, 915 participants): PCR-based LOH detected 94% of FISH-determined codeletions (95% credible interval (CrI) 83% to 98%) and FISH detected 91% of codeletions determined by PCR-based LOH (CrI 78% to 97%). Of tumours determined not to have a deletion by FISH, 94% (CrI 87% to 98%) had a deletion detected by PCR-based LOH, and of those determined not to have a deletion by PCR-based LOH, 96% (CrI 90% to 99%) had a deletion detected by FISH. The latent class analysis suggested that PCR-based LOH may be slightly more accurate than FISH. Most other techniques appeared to have high sensitivity (i.e. produced few false-negative results) for detection of 1p/19q codeletion when either FISH or PCR-based LOH was considered as the reference standard, although there was limited evidence. There was some indication of differences in specificity (false-positive rate) with some techniques. Both NGS and SNP array had high specificity when considered against FISH as the reference standard (NGS: 6 studies, 243 participants; SNP: 6 studies, 111 participants), although we rated certainty in the evidence as low or very low. NGS and SNP array also had high specificity when PCR-based LOH was considered the reference standard, although with much more uncertainty as these results were based on fewer studies (just one study with 49 participants for NGS and two studies with 33 participants for SNP array). G-banding had low sensitivity and specificity when PCR-based LOH was the reference standard. Although MS had very high sensitivity and specificity when both FISH and PCR-based LOH were considered the reference standard, these results were based on only one study with a small number of participants. Real-time PCR also showed high specificity with FISH as a reference standard, although there were only two studies including 40 participants. We found no relevant economic evaluations. Our economic model using FISH as the reference standard suggested that the resource-optimising test depends on which measure of diagnostic accuracy is most important. With FISH as the reference standard, MLPA is likely to be cost-effective if society was willing to pay GBP 1000 or less for a true positive detected. However, as the value placed on a true positive increased, CISH was most cost-effective. Findings differed when the outcome measure changed to either true negative detected or correct diagnosis. When PCR-based LOH was used as the reference standard, MLPA was likely to be cost-effective for all measures of diagnostic accuracy at lower threshold values for willingness to pay. However, as the threshold values increased, none of the tests were clearly more likely to be considered cost-effective. AUTHORS' CONCLUSIONS: In our review, most techniques (except G-banding) appeared to have good sensitivity (few false negatives) for detection of 1p/19q codeletions in glioma against both FISH and PCR-based LOH as a reference standard. However, we judged the certainty of the evidence low or very low for all the tests. There are possible differences in specificity, with both NGS and SNP array having high specificity (fewer false positives) for 1p/19q codeletion when considered against FISH as the reference standard. The economic analysis should be interpreted with caution due to the small number of studies.

摘要

背景:1 号染色体短臂完全缺失(1p)和 19 号染色体长臂缺失(19q),称为 1p/19q 缺失,是一种可发生在神经胶质瘤中的突变。它发生在一种称为少突胶质细胞瘤的神经胶质瘤及其高级别对应物间变性少突胶质细胞瘤中。检测神经胶质瘤中的 1p/19q 缺失很重要,因为它与另一种称为异柠檬酸脱氢酶的酶的突变一起,是诊断少突胶质细胞瘤所必需的。1p/19q 缺失的存在还可以告知患者的预后,并预测最佳药物治疗效果。目前使用的主要检测方法有荧光原位杂交(FISH)和基于聚合酶链反应(PCR)的杂合性丢失(LOH)检测(也称为基于 PCR 的短串联重复或微卫星分析)。还有许多其他的检测方法。但没有一种检测方法是完美的,尽管基于 PCR 的 LOH 预计具有非常高的灵敏度。 目的:评估不同脱氧核糖核酸(DNA)检测技术在确定神经胶质瘤中 1p/19q 缺失状态的敏感性、特异性和成本效益。 检索方法:我们检索了 MEDLINE、Embase 和 BIOSIS,检索时间截至 2019 年 7 月。我们没有基于语言或出版日期的限制。我们从这个搜索结果和英国国家卫生服务经济评估数据库中寻找经济评估研究。 选择标准:我们纳入了横断面研究,纳入对象为有或无任何亚型的神经胶质瘤的成年人,提供了两种或两种以上用于 1p/19q 缺失检测的 DNA 检测的原始数据或交叉表格。我们还对这些检测的经济评估进行了研究。 数据收集和分析:我们遵循了 Cochrane 诊断测试准确性综述手册中的程序。两位综述作者独立筛选标题/摘要/全文,进行数据提取,并使用 QUADAS-2 进行适用性和偏倚风险评估。使用层次汇总 ROC 模型进行荟萃分析,以估计和比较检测的准确性。我们使用 FISH 和基于 PCR 的 LOH 作为替代参考标准,以检查这些测试与常用测试的比较,并进行了潜伏类分析,以比较 FISH 和基于 PCR 的 LOH。我们构建了一个经济模型来评估成本效益。 主要结果:我们共纳入了 53 项研究,包括基于 PCR 的 LOH、FISH、单核苷酸多态性(SNP)阵列、下一代测序(NGS)、比较基因组杂交(CGH)、阵列比较基因组杂交(aCGH)、多重连接依赖性探针扩增(MLPA)、实时 PCR、显色原位杂交(CISH)、质谱(MS)、限制性片段长度多态性(RFLP)分析、G 带、甲基化阵列和 NanoString。只有一项研究的偏倚风险较低;大多数研究对患者的选择或缺失数据表示担忧。由于只纳入了特定类型的神经胶质瘤患者,我们对许多研究的适用性表示担忧。共有 1520 名参与者参与了 FISH 作为参考的分析,1304 名参与者参与了涉及 PCR 基于 LOH 的分析,262 名参与者参与了来自未包括 FISH 或 PCR 基于 LOH 的研究的方法之间的比较分析。大多数证据可用于 FISH 与基于 PCR 的 LOH 的比较(15 项研究,915 名参与者):基于 PCR 的 LOH 检测到 94%的 FISH 确定的缺失(95%可信区间[CrI]为 83%至 98%),FISH 检测到 91%的基于 PCR 的 LOH 确定的缺失(CrI 为 78%至 97%)。在 FISH 确定无缺失的肿瘤中,94%(CrI 为 87%至 98%)通过基于 PCR 的 LOH 检测到缺失,在 FISH 确定无缺失的肿瘤中,96%(CrI 为 90%至 99%)通过 FISH 检测到缺失。潜伏类分析表明,基于 PCR 的 LOH 可能比 FISH 更准确。当 FISH 或基于 PCR 的 LOH 被认为是参考标准时,大多数其他技术似乎都具有很高的敏感性(即产生的假阴性结果很少),用于检测 1p/19q 缺失,但证据有限。一些技术的特异性(假阳性率)似乎存在差异。当 FISH 被认为是参考标准时,NGS 和 SNP 阵列都具有很高的特异性(NGS:6 项研究,243 名参与者;SNP:6 项研究,111 名参与者),尽管我们将证据的确定性评为低或极低。当 PCR 基于 LOH 被认为是参考标准时,NGS 和 SNP 阵列也具有很高的特异性,尽管这些结果的不确定性更大,因为这些结果基于较少的研究(仅一项研究有 243 名参与者进行 NGS,两项研究有 33 名参与者进行 SNP 阵列)。G 带在基于 PCR 的 LOH 作为参考标准时具有较低的敏感性和特异性。虽然 MS 在 FISH 和 PCR 基于 LOH 均被认为是参考标准时具有非常高的敏感性和特异性,但这些结果仅基于一项研究,参与者人数较少。实时 PCR 也显示出与 FISH 作为参考标准时具有很高的特异性,尽管只有两项研究包括 40 名参与者。我们没有发现相关的经济评估。我们的经济模型使用 FISH 作为参考标准表明,资源优化测试取决于哪种诊断准确性衡量指标最为重要。使用 FISH 作为参考标准时,如果社会愿意支付 1000 英镑或更少的费用来检测到一个真正的阳性,那么 MLPA 可能具有成本效益。然而,随着对真正阳性的重视程度的提高,CISH 则是最具成本效益的。当使用不同的诊断准确性衡量指标时,如真正的阴性检测或正确的诊断,发现结果有所不同。当使用基于 PCR 的 LOH 作为参考标准时,在较低的支付意愿阈值下,MLPA 可能对所有衡量指标的诊断准确性都是成本有效的。然而,随着阈值的增加,没有一种测试方法被认为是明显更具成本效益的。 结论:在我们的综述中,大多数技术(除 G 带外)似乎对神经胶质瘤中 1p/19q 缺失的检测具有很好的敏感性(假阴性较少),与 FISH 和基于 PCR 的 LOH 作为参考标准一致。然而,我们对所有检测的证据确定性都评价为低或极低。可能存在特异性(假阳性率)的差异,NGS 和 SNP 阵列在考虑到 FISH 作为参考标准时具有较高的特异性(假阳性率较少)。由于研究数量较少,经济分析应谨慎解释。

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