Adjusted regression trend test for a multicenter clinical trial

Studies using a series of increasing doses of a compound, including a zero dose control, are often conducted to study the effect of the compound on the response of interest. For a one-way design, Tukey et al. (1985, Biometrics 41, 295-301) suggested assessing trend by examining the slopes of regression lines under arithmetic, ordinal, and arithmetic-logarithmic dose scalings. They reported the smallest p-value for the three significance tests on the three slopes for safety assessments. Capizzi et al. (1992, Biometrical Journal 34, 275-289) suggested an adjusted trend test, which adjusts the p-value using a trivariate t-distribution, the joint distribution of the three slope estimators. In this paper, we propose an adjusted regression trend test suitable for two-way designs, particularly for multicenter clinical trials. In a step-down fashion, the proposed trend test can be applied to a multicenter clinical trial to compare each dose with the control. This sequential procedure is a closed testing procedure for a trend alternative. Therefore, it adjusts p-values and maintains experimentwise error rate. Simulation results show that the step-down trend test is overall more powerful than a step-down least significant difference test.     

To some reasonable test procedures in multiple contingency tables to investigate certain epidemiological or medicin-sociological relationships

One of the most important tasks of the application of mathematical-statistical methods consists in giving help in the search for possible relationships, and connected with this, the specification of new hypotheses. The progress of both the special diciplines of sciences and mathematical statistics itself leads to the application of more and more complex, that means multivariate, methods. In medical fields, especially in epidemiological and medicin-sociological studies, this fact means the necessity of analysing multidimensional contingency tables. The above formulated problem is equivalent to the problem of fitting an appropriate mathematical model (for contingency tables is this a log-linear model) to the data in a way which makes the structural relationships clear to us. In this paper it is shown that one is able to get to well-interpretable models of independence with relatively simple means. Two stepwise test procedures are described yielding essentially the same results: a so called reduction procedure which is particularly profitable in sparsely occupied tables and a procedure which uses a combination of hypotheses of conditional pairwise independence.     

A staining procedure for micronucleus test using new methylene blue and acridine orange: specimens that are supravitally stained with possible long-term storage

The micronucleus test has been widely used as an in vivo cytogenetic test. It employs two different kinds of supravital staining methods which use either new methylene blue (N) and Giemsa (G) or acridine orange (AO). We have developed a new staining procedure for the preparation of specimens supravitally stained with possible long-term storage, using both N and AO. This N/AO-staining method involves three steps; (1) combination of the target tissue or target cells with an equivalent volume of 0.5% solution of new methylene blue (N-staining step), (2) immediate smear of the mixture, followed by treatment with methanol for 10 min for fixation and removal of N and drying (referred to as fixed-decolorized specimens), and (3) staining with 0.007% solution of AO for 3 min, followed by washing with Sörensen's buffer (pH 6.8) and covering of specimens before observation (AO-staining step). To examine whether the N/AO-staining method is useful for the micronucleus test, comparisons were made between N-, N/AO-, and AO-stained specimens prepared supravitally from peripheral blood of rats with and without treatment of cyclophosphamide. The results indicate that N/AO-stained specimens can be supravitally observed after long-term storage with the same coloration and comparable frequencies of micronucleated reticulocytes with a positive response as AO-stained specimens, if the staining process is temporarily stopped before AO-staining (as fixed-decolorized specimens), or if the AO-staining step is repeated. The results also showed that separated reticulocyte types are supravitally stained in a similar fashion to N-stained specimens but not to AO-stained specimens, indicative of the preservation of the supravital feature of N-staining. Taken together these results suggest that the N/AO-staining procedure could offer an additional useful staining tool for the micronucleus test.     

On weighted Hochberg procedures

We consider different ways of constructing weighted Hochberg-typestep-up multiple test procedures including closed proceduresbased on weighted Simes tests and their conservative step-upshort-cuts, and step-up counterparts of two weighted Holm procedures.It is shown that the step-up counterparts have some seriouspitfalls such as lack of familywise error rate control and lackof monotonicity in rejection decisions in terms of p-values.Therefore an exact closed procedure appears to be the best alternative,its only drawback being lack of simple stepwise structure. Aconservative step-up short-cut to the closed procedure may beused instead, but with accompanying loss of power. Simulationsare used to study the familywise error rate and power propertiesof the competing procedures for independent and correlated p-values.Although many of the results of this paper are negative, theyare useful in highlighting the need for caution when procedureswith similar pitfalls may be used.     

General multistage gatekeeping procedures

A general multistage (stepwise) procedure is proposed for dealing with arbitrary gatekeeping problems including parallel and serial gatekeeping. The procedure is very simple to implement since it does not require the application of the closed testing principle and the consequent need to test all nonempty intersections of hypotheses. It is based on the idea of carrying forward the Type I error rate for any rejected hypotheses to test hypotheses in the next ordered family. This requires the use of a so-called separable multiple test procedure (MTP) in the earlier family. The Bonferroni MTP is separable, but other standard MTPs such as Holm, Hochberg, Fallback and Dunnett are not. Their truncated versions are proposed which are separable and more powerful than the Bonferroni MTP. The proposed procedure is illustrated by a clinical trial example.     

EDTA纸片法和三维试验检测阴沟肠杆菌AmpC酶的比较

目的比较EDTA纸片法及头孢西丁三维试验检测阴沟肠杆菌AmpC酶的符合程度。方法收集近几年阴沟肠杆菌株97株临床菌株,应用EDTA纸片法和三维试验分别检测97株阴沟肠杆菌的AmpC酶,并进行比较。结果 97株受检菌中,75株EDTA纸片法和三维试验均阴性,20株两种方法均阳性,2株菌EDTA纸片法阴性,而三维试验阳性。两种检测方法阳性符合率为90.9%,阴性符合率为100%,总符合率为97.9%。结论 ED-TA纸片法检测阴沟肠杆菌与三维试验的符合率高,且操作简便,较适合于临床实验室应用。     

On identification of the number of best treatments using the Newman-Keuls test

In this paper, we provide a stochastic ordering of the Studentized range statistics under a balanced one-way ANOVA model. Based on this result we show that, when restricted to the multiple comparisons with the best, the Newman-Keuls (NK) procedure strongly controls experimentwise error rate for a sequence of null hypotheses regarding the number of largest treatment means. In other words, the NK procedure provides an upper confidence bound for the number of best treatments.     

The progress in pre-transfusion test technique research

Pre-transfusion tests include ABO/RhD blood typing, irregular antibody screening and cross-matching test, which are pivotal for safe and effective clinical transfusion. The best pre-transfusion test technology should be selected to ensure the safety of the clinical transfusion, use blood resources effectively, improve the transfusion’s effect, and achieve a precision transfusion. Here we reviewed the progress of main techniques and applications of pre-transfusion tests in recent years. aiming to give clinicians a systematic understanding of current pre-transfusion test techniques in clinical transfusion treatment.     

Application of Multiple Test Procedures to the Combination of Multivariate and Univariate Tests with Varying Variable Sets

The positive ascertainment of location differences in a multivariate comparison of two or more groups gives rise to the question for the contribution of the single variables or of subsets of variables to the multivariate difference. In this paper two methods are proposed to accomplish the original multivariate test by tests in variable subsets or in single variables using a closed test procedure and Holm's procedure, respectively. Both control the multiple level of the whole procedure.     

Adaptive seamless clinical trials using early outcomes for treatment or subgroup selection: Methods,simulation model and their implementation in R

Adaptive seamless designs combine confirmatory testing, a domain of phase III trials, with features such as treatment or subgroup selection, typically associated with phase II trials. They promise to increase the efficiency of development programmes of new drugs, for example, in terms of sample size and/or development time. It is well acknowledged that adaptive designs are more involved from a logistical perspective and require more upfront planning, often in the form of extensive simulation studies, than conventional approaches. Here, we present a framework for adaptive treatment and subgroup selection using the same notation, which links the somewhat disparate literature on treatment selection on one side and on subgroup selection on the other. Furthermore, we introduce a flexible and efficient simulation model that serves both designs. As primary endpoints often take a long time to observe, interim analyses are frequently informed by early outcomes. Therefore, all methods presented accommodate interim analyses informed by either the primary outcome or an early outcome. The R package asd , previously developed to simulate designs with treatment selection, was extended to include subgroup selection (so-called adaptive enrichment designs). Here, we describe the functionality of the R package asd and use it to present some worked-up examples motivated by clinical trials in chronic obstructive pulmonary disease and oncology. The examples both illustrate various features of the R package and provide insights into the operating characteristics of adaptive seamless studies.     

Berberine produces antidepressant-like effects in the forced swim test and in the tail suspension test in mice

This study investigated the effect of berberine (BER) in the mouse forced swim test (FST) and in the tail suspension test (TST), two models predictive of antidepressant activity. We also investigated the antidepressant-like mechanism of BER by the combination of the desipramine [DES, an inhibitor of reuptake of noradrenaline (NA) and serotonin (5-HT)], maprotiline (MAP, selective NA reuptake inhibitor), fluoxetine (FLU, selective 5-HT reuptake inhibitor) and moclobemide [MOC, monoamine oxidase (MAO) A inhibitor). Then we further measured the levels of monoamines [NA, dopamine (DA) and 5-HT) in mice striatum, hippocampus and frontal cortex. The results show that BER (10, 20 mg/kg, p.o.), significantly reduced the immobility time during the FST and the TST. The immobility time after treatment with BER (20 mg/kg, p.o.) in FST was augmented by DES, FLU and MOC, and not affected by MAP. Furthermore, BER (20 mg/kg, p.o.) increased NA and 5-HT levels in the hippocampus and frontal cortex. Our findings support the view that BER exerts antidepressant-like effect. The antidepressant-like mechanism of BER may be related to the increase in NA and 5-HT levels in the hippocampus and frontal cortex.     

Estimating the flexural rigidity of Arabidopsis inflorescence stems: Free-vibration test vs. three-point bending test

The mechanical strength of a plant stem (a load-bearing organ) helps the plant resist drooping, buckling and fracturing. We previously proposed a method for quickly evaluating the stiffness of an inflorescence stem in the model plant Arabidopsis thaliana based on measuring its natural frequency in a free-vibration test. However, the relationship between the stiffness and flexural rigidity of inflorescence stems was unclear. Here, we compared our previously described free-vibration test with the three-point bending test, the most popular method for calculating the flexural rigidity of A. thaliana stems, and examined the extent to which the results were correlated. Finally, to expand the application range, we present an example of a modified free-vibration test. Our results provide a reference for improving estimates of the flexural rigidity of A. thaliana inflorescence stems.     

A modified sign test for comparing paired ROC curves

We develop a permutation test for assessing a difference in the areas under the curve (AUCs) in a paired setting where both modalities are given to each diseased and nondiseased subject. We propose that permutations be made between subjects specifically by shuffling the diseased/nondiseased labels of the subjects within each modality. As these permutations are made within modality, the permutation test is valid even if both modalities are measured on different scales. We show that our permutation test is a sign test for the symmetry of an underlying discrete distribution whose size remains valid under the assumption of equal AUCs. We demonstrate the operating characteristics of our test via simulation and show that our test is equal in power to a permutation test recently proposed by Bandos and others (2005).