Controlling type I error rates in multi-arm clinical trials: A case for the false discovery rate.

Multi-arm trials are an efficient way of simultaneously testing several experimental treatments against a shared control group. As well as reducing the sample size required compared to running each trial separately, they have important administrative and logistical advantages. There has been debate over whether multi-arm trials should correct for the fact that multiple null hypotheses are tested within the same experiment. Previous opinions have ranged from no correction is required, to a stringent correction (controlling the probability of making at least one type I error) being needed, with regulators arguing the latter for confirmatory settings. In this article, we propose that controlling the false-discovery rate (FDR) is a suitable compromise, with an appealing interpretation in multi-arm clinical trials. We investigate the properties of the different correction methods in terms of the positive and negative predictive value (respectively how confident we are that a recommended treatment is effective and that a non-recommended treatment is ineffective). The number of arms and proportion of treatments that are truly effective is varied. Controlling the FDR provides good properties. It retains the high positive predictive value of FWER correction in situations where a low proportion of treatments is effective. It also has a good negative predictive value in situations where a high proportion of treatments is effective. In a multi-arm trial testing distinct treatment arms, we recommend that sponsors and trialists consider use of the FDR

Graphical approaches for the control of generalised error rates

When simultaneously testing multiple hypotheses, the usual approach in the context of confirmatory clinical trials is to control the familywise error rate (FWER), which bounds the probability of making at least one false rejection. In many trial settings, these hypotheses will additionally have a hierarchical structure that reflects the relative importance and links between different clinical objectives. The graphical approach of Bretz et al. (2009) is a flexible and easily communicable way of controlling the FWER while respecting complex trial objectives and multiple structured hypotheses. However, the FWER can be a very stringent criterion that leads to procedures with low power, and may not be appropriate in exploratory trial settings. This motivates controlling generalised error rates, particularly when the number of hypotheses tested is no longer small. We consider the generalised familywise error rate (k-FWER), which is the probability of making k or more false rejections, as well as the tail probability of the false discovery proportion (FDP), which is the probability that the proportion of false rejections is greater than some threshold. We also consider asymptotic control of the false discovery rate (FDR), which is the expectation of the FDP. In this paper, we show how to control these generalised error rates when using the graphical approach and its extensions. We demonstrate the utility of the resulting graphical procedures on three clinical trial case studies.Biometrika Trust; Medical Research Council, Grant/Award Numbers: MC∖UU∖00002/6, MR/N028171/

Sclero-conjunctival ischaemia secondary to intra-arterial chemotherapy for retinoblastoma

PURPOSE Intra-arterial chemotherapy (IAC), delivered directly to the globe via the internal carotid artery is now an established treatment for retinoblastoma. We report a case of anterior segment ischaemia following treatment with multiple intra-arterial chemotherapy (IAC) infusions. OBSERVATIONS A 5 month old female presented with bilateral retinoblastoma and was treated with 12 infusions of IAC. Her right eye was enucleated at diagnosis. After her seventh IAC treatment, she developed ipsilateral sixth and third cranial nerve palsies. After the twelfth IAC, she developed an area of conjunctival and scleral ischaemia between 12 and 3 o'clock meridians in her left eye. However, she maintained visual acuity of LogMAR 0.34. CONCLUSIONS AND IMPORTANCE The median number of IAC treatments in large studies is three. It is possible that repeated doses of IAC have an accumulative negative effect on the ocular blood supply, risking anterior segment and neurologic sequelae. This case highlights the significant challenge of balancing the salvage of eyes and vision with the potentially significant morbidity associated with IAC

Wavelength dependent mechanism of phenolate photooxidation in aqueous solution

Phenolate photooxidation is integral to a range of biological processes, yet the mechanism of electron ejection has been disputed. Here, we combine femtosecond transient absorption spectroscopy, liquid-microjet photoelectron spectroscopy and high-level quantum chemistry calculations to investigate the photooxidation dynamics of aqueous phenolate following excitation at a range of wavelengths, from the onset of the S0-S1 absorption band to the peak of the S0-S2 band. We find that for λ ≥ 266 nm, electron ejection occurs from the S1 state into the continuum associated with the contact pair in which the PhO˙ radical is in its ground electronic state. In contrast, we find that for λ ≤ 257 nm, electron ejection also occurs into continua associated with contact pairs containing electronically excited PhO˙ radicals and that these contact pairs have faster recombination times than those containing PhO˙ radicals in their ground electronic state

A Review of Bayesian Perspectives on Sample Size Derivation for Confirmatory Trials.

Funder: Biometrika TrustSample size derivation is a crucial element of planning any confirmatory trial. The required sample size is typically derived based on constraints on the maximal acceptable Type I error rate and minimal desired power. Power depends on the unknown true effect and tends to be calculated either for the smallest relevant effect or a likely point alternative. The former might be problematic if the minimal relevant effect is close to the null, thus requiring an excessively large sample size, while the latter is dubious since it does not account for the a priori uncertainty about the likely alternative effect. A Bayesian perspective on sample size derivation for a frequentist trial can reconcile arguments about the relative a priori plausibility of alternative effects with ideas based on the relevance of effect sizes. Many suggestions as to how such "hybrid" approaches could be implemented in practice have been put forward. However, key quantities are often defined in subtly different ways in the literature. Starting from the traditional entirely frequentist approach to sample size derivation, we derive consistent definitions for the most commonly used hybrid quantities and highlight connections, before discussing and demonstrating their use in sample size derivation for clinical trials

Sequence Skill Acquisition and Off-Line Learning in Normal Aging

It is well known that certain cognitive abilities decline with age. The ability to form certain new declarative memories, particularly memories for facts and events, has been widely shown to decline with advancing age. In contrast, the effects of aging on the ability to form new procedural memories such as skills are less well known, though it appears that older adults are able to acquire some new procedural skills over practice. The current study examines the effects of normal aging on procedural memory more closely by comparing the effects of aging on the encoding or acquisition stage of procedural learning versus its effects on the consolidation, or between-session stage of procedural learning. Twelve older and 14 young participants completed a sequence-learning task (the Serial Reaction Time Task) over a practice session and at a re-test session 24 hours later. Older participants actually demonstrated more sequence skill during acquisition than the young. However, older participants failed to show skill improvement at re-test as the young participants did. Age thus appears to have a differential effect upon procedural learning stages such that older adults' skill acquisition remains relatively intact, in some cases even superior, compared to that of young adults, while their skill consolidation may be poorer than that of young adults. Although the effect of normal aging on procedural consolidation remains unclear, aging may actually enhance skill acquisition on some procedural tasks

Unnatural amino acid analogues of membrane-active helical peptides with anti-mycobacterial activity and improved stability

Objectives The emergence of MDR-TB, coupled with shrinking antibiotic pipelines, has increased demands for new antimicrobials with novel mechanisms of action. Antimicrobial peptides have increasingly been explored as promising alternatives to antibiotics, but their inherent poor in vivo stability remains an impediment to their clinical utility. We therefore systematically evaluated unnatural amino acid-modified peptides to design analogues with enhanced anti-mycobacterial activities. Methods Anti-mycobacterial activities were evaluated in vitro and intracellularly against drug-susceptible and MDR isolates of Mycobacterium tuberculosis using MIC, killing efficacy and intracellular growth inhibition studies. Toxicity profiles were assessed against mammalian cells to verify cell selectivity. Anti-mycobacterial mechanisms were investigated using microfluidic live-cell imaging with time-lapse fluorescence microscopy and confocal laser-scanning microscopy. Results Unnatural amino acid incorporation was well tolerated without an appreciable effect on toxicity profiles and secondary conformations of the synthetic peptides. The modified peptides also withstood proteolytic digestion by trypsin. The all D-amino acid peptide, i(llkk)2i (II-D), displayed superior activity against all six mycobacterial strains tested, with a 4-fold increase in selectivity index as compared with the unmodified L-amino acid peptide in broth. II-D effectively reduced the intracellular bacterial burden of both drug-susceptible and MDR clinical isolates of M. tuberculosis after 4 days of treatment. Live-cell imaging studies demonstrated that II-D permeabilizes the mycobacterial membrane, while confocal microscopy revealed that II-D not only permeates the cell membrane, but also accumulates within the cytoplasm. Conclusions Unnatural amino acid modifications not only decreased the susceptibility of peptides to proteases, but also enhanced mycobacterial selectivity

Staphylococcus aureus in the oral cavity: a three-year retrospective analysis of clinical laboratory data

OBJECTIVE: A retrospective analysis of laboratory data to investigate the isolation of Staphylococcus aureus from the oral cavity and facial area in specimens submitted to a regional diagnostic oral microbiology laboratory. METHODS: A hand search of laboratory records for a three-year period (1998-2000) was performed for specimens submitted to the regional diagnostic oral microbiology laboratory based at Glasgow Dental Hospital and School. Data were collected from forms where S. aureus was isolated. These data included demographics, referral source, specimen type, methicillin susceptibility and clinical details. RESULTS: For the period 1998-2000, there were 5,005 specimens submitted to the laboratory. S. aureus was isolated from 1,017 specimens, of which 967 (95%) were sensitive to methicillin (MSSA) and 50 (5%) were resistant to methicillin (MRSA). The 1,017 specimens were provided from 615 patients. MRSA was isolated from 37 (6%) of patients. There was an increasing incidence of S. aureus with age, particularly in the greater than 70 years age group. The most common specimen from which MSSA was isolated was an oral rinse (38%) whilst for MRSA isolates this was a tongue swab (28%). The clinical condition most commonly reported for MSSA isolates was angular cheilitis (22%). Erythema, swelling, pain or burning of the oral mucosa was the clinical condition most commonly reported for MRSA isolates (16%). Patients from whom the MSSA isolates were recovered were most commonly (55%) seen in the oral medicine clinic at the dental hospital, whilst patients with MRSA were more commonly seen in primary care settings such as nursing homes, hospices and general dental practice (51%). CONCLUSION: In line with more recent surveys, this retrospective study suggests that S. aureus may be a more frequent isolate from the oral cavity than hitherto suspected. A small proportion of the S. aureus isolates were MRSA. There were insufficient data available to determine whether the S. aureus isolates were colonising or infecting the oral cavity. However, the role of S. aureus in several diseases of the oral mucosa merits further investigation

Requirements modelling and formal analysis using graph operations

The increasing complexity of enterprise systems requires a more advanced analysis of the representation of services expected than is currently possible. Consequently, the specification stage, which could be facilitated by formal verification, becomes very important to the system life-cycle. This paper presents a formal modelling approach, which may be used in order to better represent the reality of the system and to verify the awaited or existing system’s properties, taking into account the environmental characteristics. For that, we firstly propose a formalization process based upon properties specification, and secondly we use Conceptual Graphs operations to develop reasoning mechanisms of verifying requirements statements. The graphic visualization of these reasoning enables us to correctly capture the system specifications by making it easier to determine if desired properties hold. It is applied to the field of Enterprise modelling

Colour in urban places: A case study of Leicester City Football Club blue

By communicating an integrated story, the Leicester City Football Club blue inherits and persists the history and legacy of the football club, which further provides a stable and consistent meaning for the local sports culture. Colour as a medium and agency creates an intimacy and loyalty between the different ethnic and social groups across local, regional, and global contexts. The case study demonstrated that colour could give place identity through branding practice, identity mediation, and visual culture formation. The process reflected that economic and cultural force had a large impact on place‐making, and could be the decisive influence upon colour symbolism