Better conduct of clinical trials: the control group in critical care trials

OBJECTIVE: To review trial design issues related to control groups. DESIGN: Review of the literature with specific reference to critical care trials. MAIN RESULTS AND CONCLUSIONS: Performing randomized controlled trials in the critical care setting presents specific problems: studies include patients with rapidly lethal conditions, the majority of intensive care patients suffer from syndromes rather than from well-definable diseases, the severity of such syndromes cannot be precisely assessed, and the treatment consists of interacting therapies. Interactions between physiology, pathophysiology, and therapies are at best marginally understood and may have a major impact on study design and interpretation of results. Selection of the right control group is crucial for the interpretation and clinical implementation of results. Studies comparing new interventions with current ones or different levels of current treatments have the problem of the necessity of defining "usual care." Usual care controls without any constraints typically include substantial heterogeneity. Constraints in the usual therapy may help to reduce some variation. Inclusion of unrestricted usual care groups may help to enhance safety. Practice misalignment is a novel problem in which patients receive a treatment that is the direct opposite of usual care, and occurs when fixed-dose interventions are used in situations where care is normally titrated. Practice misalignment should be considered in the design and interpretation of studies on titrated therapies.

Continuous monitoring of bovine spongiform encephalopathy rapid test performance by weak positive tissue controls and quality control charts

Bovine spongiform encephalopathy (BSE) rapid tests and routine BSE-testing laboratories underlie strict regulations for approval. Due to the lack of BSE-positive control samples, however, full assay validation at the level of individual test runs and continuous monitoring of test performance on-site is difficult. Most rapid tests use synthetic prion protein peptides, but it is not known to which extend they reflect the assay performance on field samples, and whether they are sufficient to indicate on-site assay quality problems. To address this question we compared the test scores of the provided kit peptide controls to those of standardized weak BSE-positive tissue samples in individual test runs as well as continuously over time by quality control charts in two widely used BSE rapid tests. Our results reveal only a weak correlation between the weak positive tissue control and the peptide control scores. We identified kit-lot related shifts in the assay performances that were not reflected by the peptide control scores. Vice versa, not all shifts indicated by the peptide control scores indeed reflected a shift in the assay performance. In conclusion these data highlight that the use of the kit peptide controls for continuous quality control purposes may result in unjustified rejection or acceptance of test runs. However, standardized weak positive tissue controls in combination with Shewhart-CUSUM control charts appear to be reliable in continuously monitoring assay performance on-site to identify undesired deviations.

Improving Management of Distributed Services Using Correlations and Predictions in SLA-Driven Cloud Computing Systems

Recent advancements in cloud computing have enabled the proliferation of distributed applications, which require management and control of multiple services. However, without an efficient mechanism for scaling services in response to changing environmental conditions and number of users, application performance might suffer, leading to Service Level Agreement (SLA) violations and inefficient use of hardware resources. We introduce a system for controlling the complexity of scaling applications composed of multiple services using mechanisms based on fulfillment of SLAs. We present how service monitoring information can be used in conjunction with service level objectives, predictions, and correlations between performance indicators for optimizing the allocation of services belonging to distributed applications. We validate our models using experiments and simulations involving a distributed enterprise information system. We show how discovering correlations between application performance indicators can be used as a basis for creating refined service level objectives, which can then be used for scaling the application and improving the overall application's performance under similar conditions.

Patterns of exposure to infectious diseases and social contacts in early life and risk of brain tumours in children and adolescents: an International Case-Control Study (CEFALO)

BACKGROUND Infectious diseases and social contacts in early life have been proposed to modulate brain tumour risk during late childhood and adolescence. METHODS CEFALO is an interview-based case-control study in Denmark, Norway, Sweden and Switzerland, including children and adolescents aged 7-19 years with primary intracranial brain tumours diagnosed between 2004 and 2008 and matched population controls. RESULTS The study included 352 cases (participation rate: 83%) and 646 controls (71%). There was no association with various measures of social contacts: daycare attendance, number of childhours at daycare, attending baby groups, birth order or living with other children. Cases of glioma and embryonal tumours had more frequent sick days with infections in the first 6 years of life compared with controls. In 7-19 year olds with 4+ monthly sick day, the respective odds ratios were 2.93 (95% confidence interval: 1.57-5.50) and 4.21 (95% confidence interval: 1.24-14.30). INTERPRETATION There was little support for the hypothesis that social contacts influence childhood and adolescent brain tumour risk. The association between reported sick days due to infections and risk of glioma and embryonal tumour may reflect involvement of immune functions, recall bias or inverse causality and deserve further attention.

Distributed sensor failure detection in sensor networks

We investigate the problem of distributed sensors' failure detection in networks with a small number of defective sensors, whose measurements differ significantly from the neighbor measurements. We build on the sparse nature of the binary sensor failure signals to propose a novel distributed detection algorithm based on gossip mechanisms and on Group Testing (GT), where the latter has been used so far in centralized detection problems. The new distributed GT algorithm estimates the set of scattered defective sensors with a low complexity distance decoder from a small number of linearly independent binary messages exchanged by the sensors. We first consider networks with one defective sensor and determine the minimal number of linearly independent messages needed for its detection with high probability. We then extend our study to the multiple defective sensors detection by modifying appropriately the message exchange protocol and the decoding procedure. We show that, for small and medium sized networks, the number of messages required for successful detection is actually smaller than the minimal number computed theoretically. Finally, simulations demonstrate that the proposed method outperforms methods based on random walks in terms of both detection performance and convergence rate.

Risk factors for anal cancer in persons infected with HIV: a nested case-control study in the Swiss HIV Cohort Study

Although persons infected with human immunodeficiency virus (HIV), particularly men who have sex with men, are at excess risk for anal cancer, it has been difficult to disentangle the influences of anal exposure to human papillomavirus (HPV) infection, immunodeficiency, and combined antiretroviral therapy. A case-control study that included 59 anal cancer cases and 295 individually matched controls was nested in the Swiss HIV Cohort Study (1988-2011). In a subset of 41 cases and 114 controls, HPV antibodies were tested. A majority of anal cancer cases (73%) were men who have sex with men. Current smoking was significantly associated with anal cancer (odds ratio (OR) = 2.59, 95% confidence interval (CI): 1.25, 5.34), as were antibodies against L1 (OR = 4.52, 95% CI: 2.00, 10.20) and E6 (OR = ∞, 95% CI: 4.64, ∞) of HPV16, as well as low CD4+ cell counts, whether measured at nadir (OR per 100-cell/μL decrease = 1.53, 95% CI: 1.18, 2.00) or at cancer diagnosis (OR per 100-cell/μL decrease = 1.24, 95% CI: 1.08, 1.42). However, the influence of CD4+ cell counts appeared to be strongest 6-7 years prior to anal cancer diagnosis (OR for <200 vs. ≥500 cells/μL = 14.0, 95% CI: 3.85, 50.9). Smoking cessation and avoidance of even moderate levels of immunosuppression appear to be important in reducing long-term anal cancer risks.

Improving bovine udder health: a national mastitis control program in the Netherlands

Because of increasing bulk milk somatic cell counts and continuous clinical mastitis problems in a substantial number of herds, a national mastitis control program was started in 2005 to improve udder health in the Netherlands. The program started with founding the Dutch Udder Health Centre (UGCN), which had the task to coordinate the program. The program consisted of 2 parts: a research part and a knowledge-transfer part, which were integrated as much as possible. The knowledge-transfer part comprised 2 communication strategies: a central and a peripheral approach. The central approach was based on educating farmers using comprehensive science-based and rational argumentation about mastitis prevention and included on-farm study group meetings. Comprehensive education materials were developed for farmers that were internally motivated to improve udder health. In the peripheral approach it was tried to motivate farmers to implement certain management measures using nontechnical arguments. Mass media campaigns were used that focused on one single aspect of mastitis prevention. These communication strategies, as well as an integrated approach between various stakeholders and different scientific disciplines were used to reach as many farmers as possible. It should be noted that, because this intervention took place at a national level, no control group was available, as it would be impossible to isolate farmers from all forms of communication for 5 years. Based on several studies executed during and after the program, however, the results suggest that udder health seemed to have improved on a national level during the course of the program from 2005 to 2010. Within a cohort of dairy herds monitored during the program, the prevalence of subclinical mastitis did not change significantly (23.0 in 2004 vs. 22.2 in 2009). The incidence rate of clinical mastitis, however, decreased significantly, from 33.5 to 28.1 quarter cases per 100 cow years at risk. The most important elements of the farmers' mindset toward mastitis control also changed favorably. The simulated costs of mastitis per farm were reduced compared with a situation in which the mastitis would not have changed, with € 400 per year. When this amount is extrapolated to all Dutch farms, the sector as a whole reduced the total costs of mastitis by € 8 million per year. It is difficult to assign the improved udder health completely to the efforts of the program due to the lack of a control group. Nevertheless, investing € 8 million by the Dutch dairy industry in a 5-yr national mastitis control program likely improved udder health and seemed to pay for itself financially.

Validation of a paradigm to measure instrumental aggression (iap) on a sample of male adolescents with adjustment problems

Aggressive behavior can be classified in hostile and instrumental aggressions (anderson & bushman, 2002). this classification is mostly synonymously used with reactive and proactive aggression, whereas the differences between hostile and instrumental aggression lie on three dimensions, the primary goal, amount of anger and planning and calculation(bushman & anderson, 2001). although there are rating instruments and experimental paradigms to measure hostile aggression, there is no instrument to measure instrumental aggression. the following study will present an account to measure instrumental aggression with an experimental laboratory paradigm. the instrument was firstly tested on two samples of normal young adolescents (n1 = 100; amage. = 19.14; n2 = 60; amage. = 21.46). the first study revealed a strong correlation with a laboratory aggression paradigm measuring hostile aggression, but no correlations with self-reported aggression in the buss and perry questionnaire. these results were replicated in a second study, revealing an additional correlation with aggressive but not adaptive assertiveness. secondly the instrument was part of the evaluation of the reasoning and rehabilitation program r&r2 (ross, hilborn & lidell, 1984) in an institution for male adolescents with adjustment problems in switzerland. the r&r2 is a cognitive behavioral group therapy to reduce antisocial and promote prosocial cognitions and behavior. the treatment group (n= 16; rangeage = 15-17) is compared to a no treatment control group (n=24; rangeage = 17-19) preand post- treatment. further aggressive behavior was surveyed and experimentally measured. hostile rumination, aggressive and adaptive assertiveness, emotional and social competence were included in the measurement to estimate construct validity.

Atopic conditions and brain tumor risk in children and adolescents--an international case-control study (CEFALO)

BACKGROUND A number of epidemiological studies indicate an inverse association between atopy and brain tumors in adults, particularly gliomas. We investigated the association between atopic disorders and intracranial brain tumors in children and adolescents, using international collaborative CEFALO data. PATIENTS AND METHODS CEFALO is a population-based case-control study conducted in Denmark, Norway, Sweden, and Switzerland, including all children and adolescents in the age range 7-19 years diagnosed with a primary brain tumor between 2004 and 2008. Two controls per case were randomly selected from population registers matched on age, sex, and geographic region. Information about atopic conditions and potential confounders was collected through personal interviews. RESULTS In total, 352 cases (83%) and 646 controls (71%) participated in the study. For all brain tumors combined, there was no association between ever having had an atopic disorder and brain tumor risk [odds ratio 1.03; 95% confidence interval (CI) 0.70-1.34]. The OR was 0.76 (95% CI 0.53-1.11) for a current atopic condition (in the year before diagnosis) and 1.22 (95% CI 0.86-1.74) for an atopic condition in the past. Similar results were observed for glioma. CONCLUSIONS There was no association between atopic conditions and risk of all brain tumors combined or of glioma in particular. Stratification on current or past atopic conditions suggested the possibility of reverse causality, but may also the result of random variation because of small numbers in subgroups. In addition, an ongoing tumor treatment may affect the manifestation of atopic conditions, which could possibly affect recall when reporting about a history of atopic diseases. Only a few studies on atopic conditions and pediatric brain tumors are currently available, and the evidence is conflicting.

Control of chromosomal rearrangements in {\it Escherichia coli\/}

A complete physical map of Escherichia coli K-12 strain MG1655 was constructed by digesting chromosomal DNA with the infrequently cutting restriction enzymes NotI, SfiI and XbaI and separating the fragments by pulsed field gel electrophoresis. The map was used to compare six K-12 strains of E. coli. Although several differences were noted and localized, the map of MG1655 was representative of all the K-12 strains tested. The maps were also used to analyze chromosomal rearrangements in the E. coli strain MG1655. The spontaneous and UV induced frequencies of tandem duplication formation were measured at several loci distributed around the chromosome. The spontaneous duplication frequency varied from 10$\sp{-5}$ to 10$\sp{-3}$ and increased at least ten-fold following mild UV irradiation treatment. Duplications of several regions of the chromosome, including the serA region and the metE region, were mapped using pulsed field gel electrophoresis. Duplications of serA were found to be large, ranging in size from 600 kb to 2100 kb. Several of the duplications isolated at serA were caused by ectopic recombination between IS5 elements and between IS186 elements. Duplications of the metE region, however, were almost exclusively the result of ectopic recombination between ribosomal RNA cistrons. Duplication frequencies were determined at both serA and metE in wild type and mismatch repair mutant strains (mutL, mutS, uvrD and recF). Even though all of the mismatch repair mutations increased duplication frequency of metE, the largest increases were observed in the mutL and mutS strains. Duplication frequency of serA was increased less dramatically by mutations in mismatch repair. Several duplications of metE isolated in a wild type and a mismatch repair mutant were mapped. The results showed that the same repeated sequences were used for duplication formation in the mismatch repair mutant as were used in the wild type strain. Several isolates showed evidence of multiple rearrangements indicating that mismatch repair may play a role in stabilizing the genome by controlling chromosomal rearrangement. ^

Memory and attention problems in children with brain tumors at diagnosis

Purpose: Results from previous studies indicate that children with brain tumors (BT) might present with cognitive problems at diagnosis and thus before the start of any medical treatment. The question remains whether these problems are due to the underlying tumor itself or due to the high level of emotional and physical stress which is involved at diagnosis of a malignant disorder. All children with a de novo oncological diagnosis not involving the central nervous systems (CNS) are usually exposed to a comparable level of distress. However, patients with cancer not involving the CNS are not expected to show disease-related cognitive problems. Thus they serve as a well-balanced control group (CG) to help distinguish between the probable causes of the effect. Method: In a pilot study we analyzed an array of cognitive functions in 16 children with BT and 17 control patients. In both groups, tests were administered in-patient at diagnosis before any therapeutic intervention such as surgery, chemotherapy od irradiation. Results: Performance of children with BT was comparable to that of CG patients in the areas of intelligence, perceptual reasoning, verbal comprehension, working memory, and processing speed. In contrast, however, BT patients performded significantly worse in verbal memory and attention. Conclusion: Memory and attention seem to be the most vulnerable funstions affected by BT, with other functions being preserved at the time of diagnosis. It ist to be expected that this vulnerability might exacerbate the cognitive decline after chemotherapy and radiation treatment - known to impair intellectual performance. The findings highlight the need of early cognitive assessments in children with BT in order to introduce cognitive training as early as possible to minimize or even prevent cognitive long-term sequelae. This might improve long-term academic and professional outcome of these children, but especially helps their return to school after hospitalization.

Chlamydia Control: A Comparative Review from the USA and UK

Chlamydia trachomatis infection (chlamydia) is the most common notifiable bacterial sexually transmitted infection (STI) worldwide. In the United States of America (USA) in 2009, 1,244,180 cases of chlamydia were reported to the Centers for Disease Control and Prevention (CDC), the largest number of cases ever reported to CDC for any notifiable disease [1]. It has been estimated, from population prevalence surveys, that approximately 2 % of sexually active adults aged 18–44 years old in the UK [2] and 2.2 % (CI, 1.8–2.8 %) of the US population aged 14–39 years [3] are infected with chlamydia. This level of prevalence in the USA translates into an estimated 2,291,000 (95 % confidence interval, CI, 1,857,000–2,838,000) chlamydia infections each year [3]. Globally, the World Health Organization (WHO) estimates that there are about 92 million new cases of chlamydia each year [4].

Robust meta-analytic-predictive priors in clinical trials with historical control information.

Historical information is always relevant for clinical trial design. Additionally, if incorporated in the analysis of a new trial, historical data allow to reduce the number of subjects. This decreases costs and trial duration, facilitates recruitment, and may be more ethical. Yet, under prior-data conflict, a too optimistic use of historical data may be inappropriate. We address this challenge by deriving a Bayesian meta-analytic-predictive prior from historical data, which is then combined with the new data. This prospective approach is equivalent to a meta-analytic-combined analysis of historical and new data if parameters are exchangeable across trials. The prospective Bayesian version requires a good approximation of the meta-analytic-predictive prior, which is not available analytically. We propose two- or three-component mixtures of standard priors, which allow for good approximations and, for the one-parameter exponential family, straightforward posterior calculations. Moreover, since one of the mixture components is usually vague, mixture priors will often be heavy-tailed and therefore robust. Further robustness and a more rapid reaction to prior-data conflicts can be achieved by adding an extra weakly-informative mixture component. Use of historical prior information is particularly attractive for adaptive trials, as the randomization ratio can then be changed in case of prior-data conflict. Both frequentist operating characteristics and posterior summaries for various data scenarios show that these designs have desirable properties. We illustrate the methodology for a phase II proof-of-concept trial with historical controls from four studies. Robust meta-analytic-predictive priors alleviate prior-data conflicts ' they should encourage better and more frequent use of historical data in clinical trials.

Service Level Agreements-Driven Management of Distributed Applications in Cloud Computing Environments

Cloud Computing enables provisioning and distribution of highly scalable services in a reliable, on-demand and sustainable manner. However, objectives of managing enterprise distributed applications in cloud environments under Service Level Agreement (SLA) constraints lead to challenges for maintaining optimal resource control. Furthermore, conflicting objectives in management of cloud infrastructure and distributed applications might lead to violations of SLAs and inefficient use of hardware and software resources. This dissertation focusses on how SLAs can be used as an input to the cloud management system, increasing the efficiency of allocating resources, as well as that of infrastructure scaling. First, we present an extended SLA semantic model for modelling complex service-dependencies in distributed applications, and for enabling automated cloud infrastructure management operations. Second, we describe a multi-objective VM allocation algorithm for optimised resource allocation in infrastructure clouds. Third, we describe a method of discovering relations between the performance indicators of services belonging to distributed applications and then using these relations for building scaling rules that a CMS can use for automated management of VMs. Fourth, we introduce two novel VM-scaling algorithms, which optimally scale systems composed of VMs, based on given SLA performance constraints. All presented research works were implemented and tested using enterprise distributed applications.

Ebola virus disease outbreak in Nigeria: Transmission dynamics and rapid control.

International air travel has already spread Ebola virus disease (EVD) to major cities as part of the unprecedented epidemic that started in Guinea in December 2013. An infected airline passenger arrived in Nigeria on July 20, 2014 and caused an outbreak in Lagos and then Port Harcourt. After a total of 20 reported cases, including 8 deaths, Nigeria was declared EVD free on October 20, 2014. We quantified the impact of early control measures in preventing further spread of EVD in Nigeria and calculated the risk that a single undetected case will cause a new outbreak. We fitted an EVD transmission model to data from the outbreak in Nigeria and estimated the reproduction number of the index case at 9.0 (95% confidence interval [CI]: 5.2-15.6). We also found that the net reproduction number fell below unity 15 days (95% CI: 11-21 days) after the arrival of the index case. Hence, our study illustrates the time window for successful containment of EVD outbreaks caused by infected air travelers.