A method of estimating varietal stability for data of long-term trials

Summary A method is proposed to analyze the stability of cultivars in long-term varietal trials. The method involves the following steps: (i) regress a standard variety on environmental means; (ii) regress varieties under test on the standard variety; (iii) transform, through a procedure of reparameterization, the regression computed for each variety under test on the standard variety into the regression of the variety on environmental means. Although this method is proposed to analyze data sets from complex designs, it may also possess some advantages over conventional procedures for simpler designs.     

Inference in response-adaptive clinical trials when the enrolled population varies over time

A common assumption of data analysis in clinical trials is that the patient population, as well as treatment effects, do not vary during the course of the study. However, when trials enroll patients over several years, this hypothesis may be violated. Ignoring variations of the outcome distributions over time, under the control and experimental treatments, can lead to biased treatment effect estimates and poor control of false positive results. We propose and compare two procedures that account for possible variations of the outcome distributions over time, to correct treatment effect estimates, and to control type-I error rates. The first procedure models trends of patient outcomes with splines. The second leverages conditional inference principles, which have been introduced to analyze randomized trials when patient prognostic profiles are unbalanced across arms. These two procedures are applicable in response-adaptive clinical trials. We illustrate the consequences of trends in the outcome distributions in response-adaptive designs and in platform trials, and investigate the proposed methods in the analysis of a glioblastoma study.     

New promising high yielding cotton Bt-Variety RH-647 adapted for specific agro-climatic zone

The Bt-cotton RH-647 was developed by Cotton Research Institute CRI, Khanpur has been acknowledged for its possesses superior plant characteristics and potential to yield out under harsh agro-climatic conditions of cotton productive district of Rahimyar Khan in Bahawalpur Division and southern Punjab in 2016. RH- 647 for its novel plant structure and improved fiber quality heat and drought tolerant to withstand successfully sustain yield out in harsh, highly variable hot and dry climatic conditions of and harsh seasoned. RH-647 was developed through one-way hybridization of elite parental genotypes accompanied by pedigree selection method through gene pyramiding technique for incorporation of excellent combinations of fiber traits and CLCuV disease tolerance with higher yield potential right from F1 population. The superior plant combinations were selected in F2-F6 generations were entirely based on phenotypic plant traits and progeny yield potential in field, plant shape, number of bolls per plant, average boll weight (g) and fiber quality traits over standard varieties. The single plant progenies were selected 56 sister lines were tested for Bt-gene (Cry1 Ac) were evaluated for high yielding performance for this superior cross and finally RH-647 as superior breeding line was bulked in year 2010. The strain was evaluated in Randomized Complete Block Design in preliminary yield trials (PYT) and two years in Advance Yield Trials (AYT) trials and Zonal Varietal trials for two years. The superior line 647/10 was ensued for performance in variety attestation tests as RH-647. RH-647 performed best in two years varietal trials (NCVT and PCCT and DUS) conducted for two successive growing seasons (2014–2015 and 2015–2016). RH-647 yielded out significantly compared with standard varieties MNH-886, FH-142 and CIM 602. After completion of mandatory trials in year 2016, RH-647 was approved as new Bt. cotton variety “RH-647”. RH-647 is early in maturity with high yield potential and best suited for wheat-cotton cropping pattern. It has fluffy opening and is easy to pick, strongly tolerant to CLCuV disease, high Ginning out turn GOT% (40.2%) with improved fiber traits; staple length (28.3 mm), fiber strength (4.2ug/inch) is duly capable to fulfill all industrial requisitions.     

Thalidomide as an anti-cancer agent

Thalidomide is a glutamic acid derivative initially introduced as a sedative hypnotic nearly forty years ago. It was withdrawn following numerous reports linking it to a characteristic pattern of congenital abnormalities in babies born to mothers who used the drug for morning sickness. It has gradually been re-introduced into clinical practice over the past two decades, albeit under strict regulation, since it was found to be useful in the management of erythema nodosum leprosum and HIV wasting syndrome. Recognition of its anti-angiogenic effect led to its evaluation in the treatment of various malignancies, where angiogenesis has been shown to play an important role. Numerous clinical trials done over the past four years have confirmed the significant anti-myeloma activity of this drug. It has also shown promise in preliminary trials in the treatment of a variety of different malignant diseases. The mechanisms of its antineoplastic effects continue to be the focus of ongoing research. It has become clear that even though its anti angiogenic effects play a significant role in the anti-tumor activity, there are other properties of this drug which are responsible as well. It also possesses anti-TNF alpha activity, which has led to its evaluation in several inflammatory states. In this concise review, we briefly describe the historical background and pharmacological aspects of this drug. We have concisely reviewed the current knowledge regarding mechanisms of its anti-neoplastic activity and the results of various clinical trials in oncology.     

Sensitivity of Resistance to Net Blotch in Barley

The aim of this study was to demonstrate various methods of analysing terminal net blotch, Pyrenophora teres Drechs. f. teres Smedeg., severity data from 15 spring barleys, Hordeum vulgare L., grown in Finnish official variety trials in five environments. The analyses have been developed and used principally by plant breeders for assessing crop yield, but lend themselves to use by plant pathologists. Pyrenophora teres is the major barley phytopathogen in Finland and improved resistance to it is sought. Joint regression analysis (JRA) and an additive main effects and multiplicative interaction (AMMI) model were used to investigate the data. Statistically significant genotype by environment (GE) interaction for resistance was indicated, and this included qualitative (crossover) interactions among genotypes over environments. A stable, non-sensitive, response to net blotch over environments, combined with a low mean score for terminal severity of the disease characterized the six-row barley 'Thule' which showed statistically significant crossover interaction only with 'Tyra'. 'Kustaa' exhibited the lowest mean terminal net blotch severity, but was relatively sensitive to net blotch. 'Arve' exhibited severe terminal net blotch in all environments, was relatively sensitive to environment and exhibited no crossover interaction with other genotypes. AMMI analysis appeared to represent a useful method for analysing these disease severity data, facilitating the selection of useful sources of resistance. Plots of AMMI-adjusted mean net blotch severities against first principal component axis (PCA) scores were informative for differentiating genotype response over environments, and are therefore potentially useful to plant pathologists and barley breeders seeking to gauge and subsequently improve the resistance status of barley to net blotch.     

Field evaluation of tolerance to Tobacco streak virus in sunflower germplasm,and observations of seasonal disease spread

Strong statistical evidence was found for differences in tolerance to natural infections of Tobacco streak virus (TSV) in sunflower hybrids. Data from 470 plots involving 23 different sunflower hybrids tested in multiple trials over 5 years in Australia were analysed. Using a Bayesian Hierarchical Logistic Regression (BHLR) model for analysis provided: (a) a rigorous method for investigating the relative effects of hybrid, seasonal rainfall and proximity to inoculum source on the incidence of severe TSV disease; (b) a natural method for estimating the probability distributions of disease incidence in different hybrids under historical rainfall conditions; and (c) a method for undertaking all pairwise comparisons of disease incidence between hybrids while controlling the familywise error rate without any drastic reduction in statistical power. The tolerance identified in field trials was effective against the main TSV strain associated with disease outbreaks, TSV‐parthenium. Glasshouse tests indicate this tolerance to also be effective against the other TSV strain found in central Queensland, TSV‐crownbeard. The use of tolerant germplasm is critical to minimise the risk of TSV epidemics in sunflower in this region. We found strong statistical evidence that rainfall during the early growing months of March and April had a negative effect on the incidence of severe infection with greatly reduced disease incidence in years that had high rainfall during this period.     

Identification of DNA markers of tobacco linked to bacterial wilt resistance

Bacterial wilt caused by Ralstonia solanacearum is one of the most destructive soil-borne diseases in the world. Breeding resistant commercial varieties of tobacco is difficult because most donor candidates' resistance is controlled by polygenes. In this paper, we demonstrate the identification of useful DNA markers for bacterial wilt-resistant tobacco breeding. One hundred and seventeen markers were identified by the amplified fragment length polymorphism (AFLP) method between W6, a burley variety with resistance originating from a Japanese domestic variety, Hatano, and Michinoku 1, a commercial burley wilt-susceptible variety, using 3,072 primer combinations. These markers were analyzed in 125 doubled haploid lines, derived from F(1) hybrids between W6 and Michinoku 1, and a linkage map consisting of ten linkage groups was drawn. The resistance phenotype of each of these lines was investigated on the basis of the average of disease severity obtained from field trials over two growing cycles. Quantitative trait loci (QTL) analysis was performed on the marker phenotypes and the resistance phenotype of each line. One QTL for the bacterial wilt resistance of W6 and DNA markers associated with this QTL were identified on a linkage group consisting of 15 markers, 32 cM in length. This QTL explained more than 30% of the variance in resistance among these lines.     

Evaluation of genetic diversity of Fusarium head blight resistance in European winter wheat

Genetic diversity in relation to Fusarium head blight (FHB) resistance was investigated among 295 European winter wheat cultivars and advanced breeding lines using 47 wheat SSR markers. Twelve additional wheat lines with known FHB resistance were included as reference material. At least one SSR marker per chromosome arm, including SSR markers reported in the literature with putative associations with QTLs for FHB resistance, were assayed to give an even distribution of SSR markers across the wheat genome. A total of 404 SSR alleles were detected. The number of alleles per locus ranged from 2 to 21, with an average of 8.6 alleles. The polymorphism information content of the SSR markers ranged from 0.13 (Xwmc483) to 0.87 (Xwmc607), with an average of 0.54. Cluster analysis was performed by both genetic distance-based and model-based methods. In general, the dendrogram based on unweighted pair-group method with arithmetic averages showed similar groupings to the model-based analysis. Seven clusters were identified by the model-based method, which did not strictly correspond to geographical origin. The FHB resistance level of the wheat lines was evaluated in field trials conducted over multiple years or locations by assessing the following traits: % FHB severity, % FHB incidence, % diseased kernels, in spray inoculation trials, and % FHB spread and % wilted tips, in point inoculation trials. Association analysis between SSR markers and the FHB disease traits detected markers significantly associated with FHB resistance, including some that have not been previously reported. The percentage of variance explained by each individual marker was, however, rather low. Haplotype analysis revealed that the FHB-resistant European wheat lines do not contain the 3BS locus derived from Sumai 3. The information generated in this study will assist in the selection of parental lines in order to increase the efficiency of breeding efforts for FHB resistance.     

Analyzing Variety by Environment Data Using Multiplicative Mixed Models and Adjustments for Spatial Field Trend

The recommendation of new plant varieties for commercial use requires reliable and accurate predictions of the average yield of each variety across a range of target environments and knowledge of important interactions with the environment. This information is obtained from series of plant variety trials, also known as multi-environment trials (MET). Cullis, Gogel, Verbyla, and Thompson (1998) presented a spatial mixed model approach for the analysis of MET data. In this paper we extend the analysis to include multiplicative models for the variety effects in each environment. The multiplicative model corresponds to that used in the multivariate technique of factor analysis. It allows a separate genetic variance for each environment and provides a parsimonious and interpretable model for the genetic covariances between environments. The model can be regarded as a random effects analogue of AMMI (additive main effects and multiplicative interactions). We illustrate the method using a large set of MET data from a South Australian barley breeding program.     

Interpretation of variety × sowing date × sowing depth interaction for bean–Fusarium–Rhizoctonia pathosystem

Through this study, the sowing date?×?sowing depth?×?variety interaction for Rhizoctonia root rot (RRR) development was investigated in field trials over two growing seasons. Four-way Wald tests indicated that there was a lower RRR incidence in var. Red compared to var. White in the majority of experimental plots. At a 5?cm seeding depth, RRR incidence for plantings on 22 May and 5 June was often lower than that for 5 May date. A hierarchical cluster analysis grouped experimental plots using averages of RRR incidence, Fusarium root rot (FRR) index and the number of seeds per plant. Sowing depth influenced FRR, RRR and productivity more than variety and date factors. Comparison of clusters recognised lower disease and greater production levels for sowing on 22 May and 5 June at 5?cm depth. Thus, shallow seeding of bean varieties in late spring should be incorporated into FRR–RRR-control programmes.     

From circadian rhythms to cancer chronotherapeutics

Mammalian circadian rhythms result from a complex organization involving molecular clocks within nearly all “normal” cells and a dedicated neuroanatomical system, which coordinates the so-called “peripheral oscillators.” The core of the central clock system is constituted by the suprachiasmatic nuclei that are located on the floor of the hypothalamus. Our understanding of the mechanisms of circadian rhythm generation and coordination processes has grown rapidly over the past few years. In parallel, we have learnt how to use the predictable changes in cellular metabolism or proliferation along the 24h time scale in order to improve treatment outcome for a variety of diseases, including cancer. The chronotherapeutics of malignant diseases has emerged as a result of a consistent development ranging from experimental, clinical, and technological prerequisites to multicenter clinical trials of chronomodulated delivery schedules. Indeed large dosing-time dependencies characterize the tolerability of anticancer agents in mice or rats, a better efficacy usually results from treatment administration near the least toxic circadian time in rodent tumor models. Programmable in time multichannel pumps have allowed to test the chronotherapy concepts in cancer patients and to implement chronomodulated delivery schedules in current practice. Clinical phase I and II trials have established the feasibility, the safety, and the activity of the chronotherapy schedules, so that this treatment method has undergone further evaluation in international multicenter phase III trials. Overall, more than 2000 patients with metastatic disease have been registered in chronotherapy trials. Improved tolerability and/or better antitumor activity have been demonstrated in randomized multicenter studies involving large patient cohorts. The relation between circadian rhythmicity and quality of life and even survival has also been a puzzling finding over the recent years. An essential step toward further developments of circadian-timed therapy has been the recent constitution of a Chronotherapy cooperative group within the European Organization for Research and Treatment of Cancer. This group now involves over 40 institutions in 12 countries. It is conducting currently six trials and preparing four new studies. The 19 contributions in this special issue reflect the current status and perspectives of the several components of cancer chronotherapeutics.     

Twenty-Seven Years of Phase III Trials for Patients with Extensive Disease Small-Cell Lung Cancer: Disappointing Results

Background

Few studies have formally assessed whether treatment outcomes have improved substantially over the years for patients with extensive disease small-cell lung cancer (ED-SCLC) enrolled in phase III trials. The objective of the current investigation was to determine the time trends in outcomes for the patients in those trials.

Methods and Findings

We searched for trials that were reported between January 1981 and August 2008. Phase III randomized controlled trials were eligible if they compared first-line, systemic chemotherapy for ED-SCLC. Data were evaluated by using a linear regression analysis. Results: In total, 52 trials were identified that had been initiated between 1980 and 2006; these studies involved 10,262 patients with 110 chemotherapy arms. The number of randomized patients and the proportion of patients with good performance status (PS) increased over time. Cisplatin-based regimens, especially cisplatin and etoposide (PE) regimen, have increasingly been studied, whereas cyclophosphamide, doxorubicin, and vincristine–based regimens have been less investigated. Multiple regression analysis showed no significant improvement in survival over the years. Additionally, the use of a PE regimen did not affect survival, whereas the proportion of patients with good PS and the trial design of assigning prophylactic cranial irradiation were significantly associated with favorable outcome.

Conclusions and Significance

The survival of patients with ED-SCLC enrolled in phase III trials did not improve significantly over the years, suggesting the need for further development of novel targets, newer agents, and comprehensive patient care.     

Retrospective analysis of the relationships among the test environments of the Southern Queensland sugarcane breeding programme

Repeatability of aspects of genotype by environment (GxE) interactions is an important factor to be assessed in designing more efficient selection programmes. Sugar yield data from multi environment trials (METs) which were part of the sugarcane breeding programme in southern Queensland were analysed. Data were obtained from 71 environments consisting of trials planted from 1986 to 1989. Retrospective analysis on these data was conducted to assess the repeatability of the clone by environment (CxE) interactions over locations and years. This analysis focussed on identifying similarities among test environments in the way they discriminated among clones for sugar yield. Analyses of variance and pattern analyses on environments over years based on standardised data were conducted. The pattern analyses were done sequentially according to the accumulated data sets over years. Squared Euclidean distances among environments were averaged over data sets and years before pattern analyses across the data sets were conducted. A graphical methodology was developed to present the results of the cumulative historical analysis. CxE interactions of a magnitude which affected selection decisions were present in each data set studied. Pattern analyses on cumulative data sets identified environmental groupings that were based on geographical positions. Each location generated a different pattern of discrimination among the clones. These results emphasised the importance of clone by location (CxL) interactions in southern Queensland and the need to concentrate more on testing across locations than on ratooning ability within a location. The classifications identified similarities among ratoon crops within a location, differences among locations and differences between ratoon crops and their plant crop (PC). This suggested that some aspects of CxL and clone by crop-year (CxY) interactions were repeatable across years. The potential applications of these results to increase efficiency of the sugarcane breeding programme, such as the possibility of applying indirect selection among environments generating similar discrimination among clones, are discussed.Abbreviations GxE Genotype-by-environment interactions - METs multi-environment trials - CxE clone-by-en-vironment interactions - CxL clone-by-location interactions - PC plant crop - CxY clone-by-crop-year interactions - CxLxF clone-by-location-by-crop-year interactions - SYT substation yield trials - BSES Bureau of SugarExperiment Stations     

Inference for the effect of treatment on survival probability in randomized trials with noncompliance and administrative censoring

In many clinical studies with a survival outcome, administrative censoring occurs when follow-up ends at a prespecified date and many subjects are still alive. An additional complication in some trials is that there is noncompliance with the assigned treatment. For this setting, we study the estimation of the causal effect of treatment on survival probability up to a given time point among those subjects who would comply with the assignment to both treatment and control. We first discuss the standard instrumental variable (IV) method for survival outcomes and parametric maximum likelihood methods, and then develop an efficient plug-in nonparametric empirical maximum likelihood estimation (PNEMLE) approach. The PNEMLE method does not make any assumptions on outcome distributions, and makes use of the mixture structure in the data to gain efficiency over the standard IV method. Theoretical results of the PNEMLE are derived and the method is illustrated by an analysis of data from a breast cancer screening trial. From our limited mortality analysis with administrative censoring times 10 years into the follow-up, we find a significant benefit of screening is present after 4 years (at the 5% level) and this persists at 10 years follow-up.     

Selecting the smoothing parameter for estimation of slowly changing evoked potential signals

Brain evoked potential (EP) data consist of a true response ("signal") and random background activity ("noise"), which are observed over repeated stimulus presentations ("trials"). A signal that changes slowly from trial to trial can be estimated by smoothing across trials and over time within trials. We present a method for selecting the smoothing parameter by minimizing an estimate of the mean average squared error (MASE). We evaluate the performance of this method using simulated EP data, and apply the method to an example set of real flash evoked potentials.     

Antibiotic treatment of atherosclerosis

PURPOSE OF REVIEW: Several lines of evidence have demonstrated an association between a variety of chronic bacterial infections and atherosclerotic cardiovascular disease. This has led to the proposal that antibiotic therapy might be helpful in the secondary prevention of atherosclerosis. A variety of smaller pilot studies have been reported testing this hypothesis and several large multicenter trials are also underway. The purpose of this review is to summarize the results of these studies and comment on their implications for the treatment of atherosclerosis. RECENT FINDINGS: Most of the antibiotic studies to date have been secondary prevention studies that have targeted patients exposed to Chlamydia pneumoniae. Most have used either azithromycin or roxithromycin with treatment courses ranging from a few days to 3 months. Several small studies of coronary artery disease patients have shown significant promise for reducing cardiovascular events such as death, myocardial infarction, or admission for unstable angina. However, other studies have not been so positive. Weekly Intervention with Zithromax for Atherosclerosis and its Related Disorders, WIZARD, the largest study to date, in which stable post-myocardial infarction patients were randomized to receive a 3-month course of azithromycin or placebo, demonstrated a significant reduction in death and myocardial infarction by 6 months, but this benefit was not sustained throughout the remaining course of follow-up. The Azithromycin and Coronary Events (ACES) and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trials are ongoing and are testing the effect of more prolonged treatment duration. SUMMARY: A variety of antibiotic trials for the secondary prevention of atherosclerosis have been performed. Several pilot studies have shown significant positive clinical effects, but, thus far, no large randomized trial has confirmed those findings. Some concerns over the antibiotics chosen and the duration of treatment have been raised. Other trials are underway to address some of those concerns. In the meantime, no recommendation for the use of antibiotic therapy for the secondary prevention of atherosclerosis can yet be made.     

西南区玉米品种的产量性能及稳定性评价的秩次分析法

用秩次分析法分别对参加2003-2005年中国西南区玉米区域试验1组和2组的各品种进行产量性能和稳产性评价.结果表明,1组25个品种中中单808、渝单8号和遵玉8号表现高产且稳定性强,辽127和YA04273表现高产但稳定性中等.2组29个品种中DH3831、GM4095和鑫丰1号表现高产且稳定性强,承玉15、东4243、X1152A、DH3838、DH3632和奥试3202表现高产但稳定性中等.其中,中单808、渝单8号、遵玉8号、辽127、DH3831、东4243、X1152A、DH3838、DH3632和奥试3202这些品种分别在2004年和2005年通过国家审定,在实践上证明秩次分析法能客观、公正地对品种的产量性能和稳定性进行评价.建议用加权法计算品种秩次平均数和秩次方差的平均数、标准差和50%置信度的置信下限和置信上限.     

The assessment of field trials in GMO research around the world and their possible integration in field trials for variety registration

Most regulations worldwide stipulate that a new genetically modified (GM) crop event has to be compared to its closest non-GM counterpart as a corner stone of the pre-market risk assessment. To this end the GM crop and its comparator should be grown in field trials for a phenotypic comparison as well as for subsequent detailed analysis of the composition of the two crop varieties. A more in-depth globally harmonised approach for the conduct of these field trials is lacking. Only a few countries have formulated detailed protocols for the set-up of GM field trials. In some countries, commercial non-GM reference varieties need to be included in a field study to compile reliable data that indicate the range of natural variation for the compounds tested at the specific location. Detailed analysis of pre-market assessment reports have so far not shown the added value of including these reference varieties in the field trials. In all cases where specific values were found to be outside of the range of the reference varieties, it proved possible to draw conclusions on the part of the pre-market risk assessment that relates to the compositional analysis, on the basis of already available compositional data. With the increasing quality of several databases on compositional data of a growing number of crop species, it seems unlikely that reference varieties will become more important on future occasions. It was furthermore investigated whether this part of the risk assessment can be related to field trial requirements for variety registration with the explicit intention of reducing the data burden on producers of new GM plant varieties. Field trials for variety registration so far include an assessment of phenotypic characteristics that do not cover safety aspects, with the exception of establishment of the glycoalkaloid content in potatoes in the Netherlands and Sweden. It may, however, under certain conditions be relatively easy to exchange data from compositional measurements between variety registration and GM testing procedures, thus laying a foundation for testing the feasibility of combining both pre-market assessment procedures in a single pre-market evaluation path.     

Prediction of individual long-term outcomes in smoking cessation trials using frailty models

In smoking cessation clinical trials, subjects commonly receive treatment and report daily cigarette consumption over a period of several weeks. Although the outcome at the end of this period is an important indicator of treatment success, substantial uncertainty remains on how an individual's smoking behavior will evolve over time. Therefore it is of interest to predict long-term smoking cessation success based on short-term clinical observations. We develop a Bayesian method for prediction, based on a cure-mixture frailty model we proposed earlier, that describes the process of transition between abstinence and smoking. Specifically we propose a two-stage prediction algorithm that first uses importance sampling to generate subject-specific frailties from their posterior distributions conditional on the observed data, then samples predicted future smoking behavior trajectories from the estimated model parameters and sampled frailties. We apply the method to data from two randomized smoking cessation trials comparing bupropion to placebo. Comparisons of actual smoking status at one year with predictions from our model and from a variety of empirical methods suggest that our method gives excellent predictions.     

Incorporating Surrogate Endpoints into Group Sequential Trials

Recent developments proposed by Lin (1991) which allow for the sequential analysis of multivariate failure time data, are discussed in the context of clinical trials with marker process data. In particular, a marker based response observed as a univariate failure time variable is considered in a univariate manner and in combination with the primary failure time variable through global measures of treatment effect. A weighting scheme is introduced that is designed to make greater use of the marker process responses when they are consistent with the responses for the primary endpoint. Univariate analyses and analyses based on global test statistics are evaluated with respect to duration of study and type I and type II error rates for a variety of relative risk parameter configurations. The simulation study is designed to extend the work of Machado, Gail and Ellenberg (1990) to sequential trials and to assess the performance of the global test statistics in this context. The global measures are found to be preferable over the univariate primary endpoint analyses when the treatment affects all transition intensities in a consistent manner. Further, there are advantages over the univariate marker based analysis when the treatment effects on some transition intensities are in opposite directions. Such a scenario remains problematic however with the relative error rates determined to a large extent by the baseline weighting scheme.