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91.
《Statistics In Biopharmaceutical Research》2013,5(4):293-310
The most frequently seen adaptation of a clinical trial design in regulatory submission is adaptation of statistical information, for example, sample size or number of events. Such adaptation can be based solely on the clinical endpoint of interest or early biomarker. In this article, we articulate the technical merits and discuss challenges when statistical information based solely on the clinical endpoint is used as the design aspect for adaptation. We present the interplay between the weighted and unweighted adaptive Z-statistics with, versus without, additional criteria. We contrast Fisher's p-value product test and the modified version to the adaptive weighted Z-test to elucidate a way to minimize the potential heterogeneity of the observed treatment effects between stages in a two-stage adaptive design setting. Another framework pertains when one is using shorter-term biomarker data for adaptation of statistical information, where the final analysis is to test the null hypothesis of no treatment effect based on the ultimate clinical outcome. It has been argued that under such a framework, no additional Type I error rate control is needed for the final analysis since the clinical endpoint is not used for adaptation. However, we show analytically that, for such an adaptation, the maximum Type I error probability can be far greater than the conventional Type I error level. We conclude by providing a few recommendations. 相似文献
92.
The validity of meta-analyses has recently been examined by comparing their results with those of megatrials on the same topic. We investigated the reliability of this gold standard by identifying megatrials, defined as ones involving more than 1000 subjects, in the recent issue of the Cochrane Library and in the article by LeLorier et al. (N Engl J Med 1997;337:536–42). In the former set, 289 pairs of megatrials were identified which studied the same patient-intervention-outcome combinations. Of these, 210 (73%, 95% CI: 67–77%) reported odds ratios or weighted mean differences that were not statistically significantly different from each other. The agreement of statistical conclusions regarding outcomes was a quadratic weighted kappa of 0.40 (95% CI: 0.29–0.51). The article by LeLorier et al. yielded 133 comparisons, of which 97 (73%, 95% CI: 64–79%) reported mutually compatible odds ratios. The agreement of statistical conclusions was a kappa of 0.33 (95% CI: 0.18–0.47). Agreement among megatrials was approximately as large as that reported between meta-analyses and megatrials. These findings suggest that taking megatrials as the gold standard can be problematic and that there is no substitute for clear and hard thinking for any study, be it a meta-analysis or a megatrial. 相似文献
93.
Florian Lordick William Allum Fátima Carneiro Emmanuel Mitry Josep Tabernero Patrick Tan Eric Van Cutsem Cornelis van de Velde Andrés Cervantes 《Cancer treatment reviews》2014
Although the incidence of gastric cancer has fallen steadily in developed countries over the past 50 years, outcomes in Western countries remain poor, primarily due to the advanced stage of the disease at presentation. While earlier diagnosis would help to improve outcomes for patients with gastric cancer, better understanding of the biology of the disease is also needed, along with advances in therapy. Indeed, progress in the treatment of gastric cancer has been limited, mainly because of its genetic complexity and heterogeneity. As a result, there is an urgent need to apply precision medicine to the management of the disease in order to ensure that individuals receive the most appropriate treatment. This article suggests a number of strategies that may help to accelerate progress in treating patients with gastric cancer. Incorporation of some of these approaches could help to improve the quality of life and survival for patients diagnosed with the disease. Standardisation of care across Europe through expansion of the European Registration of Cancer Care (EURECCA) registry – a European cancer audit that aims to improve quality and decrease variation in care across the region – may also be expected to lead to improved outcomes for those suffering from this common malignancy. 相似文献
94.
肝星状细胞(HSC)激活为肌成纤维细胞(MFB)并合成大量细胞外基质被认为是肝纤维化的核心机制。但新近研究表明肝纤维化中的MFB有相当多的补充来源,包括骨髓源性纤维细胞进入受损肝组织,循环中的单核细胞亚群向纤维细胞分化,以及肝细胞和胆管细胞的上皮一间质转化等。这些发现扩充了肝纤维化的发生机制,并可能提供新的诊断和治疗选择。 相似文献
95.
目的探讨心肌梗死1周后梗死边缘区心肌细胞快钠通道电流(INa)跨壁异质性的变化。方法30只兔随机分为3组,其中两组结扎家兔左前降支建立心肌梗死动物模型,分别为心肌梗死组和假手术对照组,另一组为正常对照组。1周后,用膜片钳技术研究左心室梗死边缘区三层心肌细胞INa的改变。结果正常对照组左室三层细胞的钠电流存在异质性,M细胞的峰值INa是心内膜和心外膜细胞的2倍多;M细胞的INa失活最快;对照组与假手术组无明显差别。心肌梗死组三层细胞的INa I—V曲线均上移,以M细胞变化最显著,INa稳态失活曲线均左移,以心外膜细胞变化最显著。结论左室心肌细胞的INa存在跨壁异质性;心肌梗死对INa的跨壁异质性有明显影响。 相似文献
96.
Speer MC Graham FL Bonner E Collier K Stajich JM Gaskell PC Pericak-Vance MA Vance JM 《Neurogenetics》2002,4(2):83-85
As part of an on-going genomic screen of unlinked Charcot-Marie-Tooth disease type 2 (CMT2) families, we identified 11 regions
in the genome with lod scores ≥1.0. One of these regions was near the recently identified CMTDI1 locus on 19q. We show evidence of linkage of DUK 1118 to this region and our data reduce the minimum candidate interval for
CMTDI1 to the 9-cM interval spanned by D19S586 and D19S432.We also demonstrate that five additional CMT2 families are unlinked to 19q markers, providing further evidence of CMT2 heterogeneity.
Electronic Publication 相似文献
97.
John L. Moran MBBS FRACP Patricia J. Solomon PhD David E. Warn PhD 《Health services & outcomes research methodology》2004,5(3-4):207-226
Methodological aspects of meta-analytic practice, heterogeneity, publication bias, metaregression and effect metric, were investigated in 14 meta-analyses reflecting major therapeutic concern in Critical Care practice. Compared with the standard Q test, the exact Zelen test was more sensitive in identifying heterogeneity. Assessment of heterogeneity impact by the I 2 statistic was consistent with inferences afforded by both the Q and Zelen test. Publication bias was subject to test and metric determination: funnel plots exhibited variable asymmetry across studies and between metrics; the regression asymmetry test appeared more sensitive than the rank correlation test; the “trim and fill” method was the most sensitive, but suggested, on the basis of quantification of the effects of potentially missing studies, that meta-analyses may be resistant to such missingness. Metaregression of treatment effect against control risk using Bayesian hierarchical regression in all metrics (log odds ratio, log risk ratio and RD) suggested that naïve linear regression approaches over-diagnosed significant relationships and exhibited regression dilution. Heterogeneity, publication bias and risk related treatment effects all demonstrate estimator and metric dependence; the RD metric would appear the most capricious in this regard. 相似文献
98.
In order to determine whether the growth of ras oncogene-transformed cells and nontransformed cells was inhibited differently by the chemotherapuetic drug cytosine arabinoside
(Ara-C) their growth was analyzed by a novel colony-based assay that is sensitive and appropriate for heterogeneous cell populations.
Colonies of nontransformed NIH3T3 cells, or ras onco- gene-transformed NIH(ras) cells, were grown in the absence of drug and then divided into subclones. Subclones were allowed to continue to grow in
the absence or presence of drug. Growth inhibition was determined by comparing the growth of drug-treated subclones with the
growth of related untreated subclones. Colonies of nontransformed cells grown in the absence of the drug displayed a large
variation in growth, and when grown in the presence of the drug displayed a large variation in growth inhibition. Colonies
of transformed cells also displayed a large variation in the absence and presence of the drug. For each cell line, related
subclones were more similar to each other than to unrelated subclones, implying inheritance of growth rates and drug response.
For NIH3T3 cells, the growth of subclones in the presence of drug was highly correlated with the growth of related subclones
in the absence of drug. However, for NIH3T3(ras) cells the growth of subclones in the presence of drug was not correlated with the growth of related subclones in the absence
of drug. Therefore, ras oncogene-transformed and nontransformed cell populations differ in their response to Ara-C.
Received: 3 November 1995/Accepted: 30 July 1996 相似文献
99.
Akifumi Kuwabara Hidenobu Watanabe Yoichi Ajioka Kazuhiro Yasuda Hidetoshi Saito Keiji Matsuda Hiroshi Kijima Katuyoshi Hatakeyama 《Cancer science》1998,89(1):40-46
The aim of this study was to clarify whether or not the status of gene alteration is heterogeneous in intramucosal carcinoma and homogeneous within invasive carcinoma. We selected 10 colorectal carcinoma cases (1 mucosal, 5 submucosal and 4 advanced carcinomas including 2 cases with lymph node metastasis) and analyzed the p53 gene sequence. Six colorectal cancers in this study showed heterogeneity in p53 mutations in cells from the intramucosal part. In the invasive part of a carcinoma, p53 mutation status was homogeneous intratumorally in all cases. These data indicate that, in regard to p53 gene alterations, colorectal cancers can be composed of various subclones when limited to the mucosa, but clonal selection occurs when one of these subclones commences invasion to the submucosa, generating a monoclonal invasive carcinoma. 相似文献
100.
In congenital nephrogenic diabetes insipidus (NDI) blunted responses of plasma factor VIII, von Willebrand factor, and plasminogen activator to the synthetic V2 analogue 1-desamino-8-d-arginine vasopressin (DDAVP) have been reported. In addition, vasodilatory responses to DDAVP appear to be absent in NDI. We describe a boy, who presented shortly after birth with the typical features of NDI, but who showed normal coagulation, fibrinolytic and vasodilatory responses to DDAVP. We conclude that in this patient the defect is confined to the kidney, while in other NDI patients there may be a general V2 receptor abnormality. These findings point to heterogeneity in NDI. 相似文献