Assessing the value-adding impact of diagnostic-type tests on drug development and marketing

OBJECTIVE AND METHODS: We explore the cash value of the companion diagnostics opportunity from the perspective of the pharmaceutical partner. Cashflow-based modeling is used to demonstrate the potential financial benefits of key relationships between the pharmaceutical and diagnostics industries. RESULTS: In four scenarios, the uplift in the net present value (NPV) of a proprietary medicine can exceed $US1.8 billion. By simple extrapolation, the uplifted NPV calculations allow realistic and plausible estimates of the companion diagnostic opportunity to be in the region of $US40 billion to $US90 billion. CONCLUSION: It is expected that such market valuation could drive a macroeconomic change that shifts healthcare practice from reactionary disease-treatment to proactive health maintenance.     

防尘螨药物的实验室药效测试方法

建立防螨药物的药效测试装置与操作方法很有必要。由于尘螨形体微小 ,给防螨药效测试的操作带来诸多困难 ,作者利用螨虫的生物习性及特点 ,建立了布块集螨法、成螨自动分离与净化法、标定计数法 ,布块浸水计数法以及螨虫的驱避和杀灭效果的测试装置与测试方法。结果表明 ,采用成螨自动分离与净化法获得的成螨比例为 ( 94 0± 1 7) %;采用标定计数的精度 (成螨数 刻度 )为 ( 2 0 4± 6 6)只。标定计数 1 0 0 0只螨的实际回收率平均为 ( 75 9± 1 4 6) %,与手工计数无显著性差别 (P >0 0 5 )。实践表明 ,此技术与方法操作简便 ,结果可靠 ,使测试的速度及效果有明显提高     

Collective effects in traffic on bi-directional ant trails

Motivated by recent experimental work of Burd et al., we propose a model of bi-directional ant traffic on pre-existing ant trails. It captures in a simple way some of the generic collective features of movements of real ants on a trail. Analysing this model, we demonstrate that there are crucial qualitative differences between vehicular- and ant-traffics. In particular, we predict some unusual features of the flow rate that can be tested experimentally. As in the uni-directional model a non-monotonic density-dependence of the average velocity can be observed in certain parameter regimes. As a consequence of the interaction between oppositely moving ants the flow rate can become approximately constant over some density interval.     

Evidence supporting predicted metabolic pathways for Vibrio cholerae: gene expression data and clinical tests

Vibrio cholerae, the etiological agent of the diarrheal illness cholera, can kill an infected adult in 24 h. V.cholerae lives as an autochthonous microbe in estuaries, rivers and coastal waters. A better understanding of its metabolic pathways will assist the development of more effective treatments and will provide a deeper understanding of how this bacterium persists in natural aquatic habitats. Using the completed V.cholerae genome sequence and PathoLogic software, we created VchoCyc, a pathway-genome database that predicted 171 likely metabolic pathways in the bacterium. We report here experimental evidence supporting the computationally predicted pathways. The evidence comes from microarray gene expression studies of V.cholerae in the stools of three cholera patients [D. S. Merrell, S. M. Butler, F. Qadri, N. A. Dolganov, A. Alam, M. B. Cohen, S. B. Calderwood, G. K. Schoolnik and A. Camilli (2002) Nature, 417, 642-645.], from gene expression studies in minimal growth conditions and LB rich medium, and from clinical tests that identify V.cholerae. Expression data provide evidence supporting 92 (53%) of the 171 pathways. The clinical tests provide evidence supporting seven pathways, with six pathways supported by both methods. VchoCyc provides biologists with a useful tool for analyzing this organism's metabolic and genomic information, which could lead to potential insights into new anti-bacterial agents. VchoCyc is available in the BioCyc database collection (http://BioCyc.org).     

Prediction of drug efficacy for cancer treatment based on comparative analysis of chemosensitivity and gene expression data

The NCI60 database is the largest available collection of compounds with measured anti-cancer activity. The strengths and limitations for using the NCI60 database as a source of new anti-cancer agents are explored and discussed in relation to previous studies. We selected a sub-set of 2333 compounds with reliable experimental half maximum growth inhibitions (GI(50)) values for 30 cell lines from the NCI60 data set and evaluated their growth inhibitory effect (chemosensitivity) with respect to tissue of origin. This was done by identifying natural clusters in the chemosensitivity data set and in a data set of expression profiles of 1901 genes for the corresponding tumor cell lines. Five clusters were identified based on the gene expression data using self-organizing maps (SOM), comprising leukemia, melanoma, ovarian and prostate, basal breast, and luminal breast cancer cells, respectively. The strong difference in gene expression between basal and luminal breast cancer cells was reflected clearly in the chemosensitivity data. Although most compounds in the data set were of low potency, high efficacy compounds that showed specificity with respect to tissue of origin could be found. Furthermore, eight potential topoisomerase II inhibitors were identified using a structural similarity search. Finally, a set of genes with expression profiles that were significantly correlated with anti-cancer drug activity was identified. Our study demonstrates that the combined data sets, which provide comprehensive information on drug activity and gene expression profiles of tumor cell lines studied, are useful for identifying potential new active compounds.     

A note on the tests for clustered matched-pair binary data

McNemar's test is used to assess the difference between two different procedures (treatments) using independent matched-pair data. For matched-pair data collected in clusters, the tests proposed by Durkalski et al. and Obuchowski are popular and commonly used in practice since these tests do not require distributional assumptions or assumptions on the structure of the within-cluster correlation of the data. Motivated by these tests, this note proposes a modified Obuchowski test and illustrates comparisons of the proposed test with the extant methods. An extensive Monte Carlo simulation study suggests that the proposed test performs well with respect to the nominal size, and has higher power; Obuchowski's test is most conservative, and the performance of the Durkalski's test varies between the modified Obuchowski test and the original Obuchowski's test. These results form the basis for our recommendation that (i) for equal cluster size, the modified Obuchowski test is always preferred; (ii) for varying cluster size Durkalski's test can be used for a small number of clusters (e.g. K < 50), whereas for a large number of clusters (e.g. K ≥ 50) the modified Obuchowski test is preferred. Finally, to illustrate practical application of the competing tests, two real collections of clustered matched-pair data are analyzed.     

FDR control by the BH procedure for two-sided correlated tests with implications to gene expression data analysis

The multiple testing problem attributed to gene expression analysis is challenging not only by its size, but also by possible dependence between the expression levels of different genes resulting from coregulations of the genes. Furthermore, the measurement errors of these expression levels may be dependent as well since they are subjected to several technical factors. Multiple testing of such data faces the challenge of correlated test statistics. In such a case, the control of the False Discovery Rate (FDR) is not straightforward, and thus demands new approaches and solutions that will address multiplicity while accounting for this dependency. This paper investigates the effects of dependency between bormal test statistics on FDR control in two-sided testing, using the linear step-up procedure (BH) of Benjamini and Hochberg (1995). The case of two multiple hypotheses is examined first. A simulation study offers primary insight into the behavior of the FDR subjected to different levels of correlation and distance between null and alternative means. A theoretical analysis follows in order to obtain explicit upper bounds to the FDR. These results are then extended to more than two multiple tests, thereby offering a better perspective on the effect of the proportion of false null hypotheses, as well as the structure of the test statistics correlation matrix. An example from gene expression data analysis is presented.     

Comparative mycobactericidal efficacy of chemical disinfectants in suspension and carrier tests

The efficacy of nine disinfectants on Mycobacterium smegmatis was tested in the presence of sputum, using quantitative suspension and carrier tests. Glutaraldehyde, povidone iodine, and chlorhexidine gluconate produced at least a 6-log10 reduction in CFU in all tests. Four disinfectants (sodium dichloroisocyanurate, phenol, ethanol, and sodium hypochlorite) were not as effective in the carrier tests as in the suspension tests; this difference ranged from a 1- to a 5-log10 reduction in CFU. The efficacy of ethanol and sodium hypochlorite was further reduced (3- and 1-log10 reductions in CFU, respectively) in the presence of sputum. The quaternary ammonium compound and iodophor were ineffective in all tests. The findings of this study demonstrate the need for a quantitative carrier test such as the one presented here.     

Time-of-day effects on cognition in preadolescents: a trails study

Cognitive performance fluctuates during the day due to diurnal variations in alertness level. This study examined: (1) whether cognitive performance in school-aged children is affected by time-of-day; (2) which functional domains are particularly vulnerable to time-of-day effects; and (3) whether the effects are more pronounced for cognitively more demanding tasks or task conditions. Children, aged 10-12 yrs, were randomly assigned to a test session starting either at 08:30 (n?=?802), 10:00 (n?=?713), or 13:00?h (n?=?652). Speed and accuracy of information processing were evaluated by tasks that assess input-related cognitive processes (e.g., stimulus encoding), central cognitive processes (e.g., working memory, sustained attention), and output-related processes (e.g., response organization) using the Amsterdam Neuropsychological Tasks program. Time-of-day effects in children were identified in specific neurocognitive domains, such as visuospatial processing and working memory, but only under cognitively more demanding task conditions. Sustained attention showed a speed-accuracy tradeoff with increased slowness and lapses in the early morning, but with better feedback responsiveness and perceptual sensitivity than in the early afternoon. Furthermore, there was a significant interaction of time-on-task with time-of-day for tempo, with the afternoon group increasing in tempo with time-on-task, and the early-morning group first showing a slowing of tempo with time-on-task, followed at the end of the task by a speed increase towards the initial levels. To conclude, the authors found time-of-day effects in preadolescents, which were confined to cognitively more demanding tasks tapping input-related and central cognitive processes.     

硫普罗宁治疗慢性乙型肝炎的临床疗效对照研究

目的：评价硫普罗宁治疗慢性乙型肝炎的效果及安全性。方法：慢性乙型肝炎80例,随机分为两组。治疗组40例,以硫普罗宁0.2g加入5%葡萄糖溶液250ml中静滴,1次/日,连续治疗4周,对照组40例,以甘草酸二铵150mg加入5%葡萄糖溶液250ml中静滴,1次/日,连续治疗4周;同时分别监测肝功能指标：丙氨酸氨基转移酶（ALT）,天冬氨酸转移酶（AST）、总蛋白（TP）、总胆红素（TBi）、肝纤维化指标（HA、PCⅢ）及凝血酶原活动度（PTA）等,并进行比较分析。结果：硫普罗宁治疗组较对照组在肝功能复常方面显示良好的治疗效应,可使转氨酶及HA明显下降,两组显效率分别为50%（20/40）和25%（10/40）,总有效率为85%（34/40）和47.5%（19/40）,两组比较差异有显著性（p〈0.01）。结论：短期临床研究提示硫普罗宁治疗慢性乙型肝炎,可明显改善肝脏功能,有抗纤维化作用,且副作用少,疗效显著。