A new approach for sizing trials with composite binary endpoints using anticipated marginal values and accounting for the correlation between components

Composite binary endpoints are increasingly used as primary endpoints in clinical trials. When designing a trial, it is crucial to determine the appropriate sample size for testing the statistical differences between treatment groups for the primary endpoint. As shown in this work, when using a composite binary endpoint to size a trial, one needs to specify the event rates and the effect sizes of the composite components as well as the correlation between them. In practice, the marginal parameters of the components can be obtained from previous studies or pilot trials, however, the correlation is often not previously reported and thus usually unknown. We first show that the sample size for composite binary endpoints is strongly dependent on the correlation and, second, that slight deviations in the prior information on the marginal parameters may result in underpowered trials for achieving the study objectives at a pre-specified significance level. We propose a general strategy for calculating the required sample size when the correlation is not specified, and accounting for uncertainty in the marginal parameter values. We present the web platform CompARE to characterize composite endpoints and to calculate the sample size just as we propose in this paper. We evaluate the performance of the proposal with a simulation study, and illustrate it by means of a real case study using CompARE

Cuts and flows of cell complexes

We study the vector spaces and integer lattices of cuts and flows associated with an arbitrary finite CW complex, and their relationships to group invariants including the critical group of a complex. Our results extend to higher dimension the theory of cuts and flows in graphs, most notably the work of Bacher, de la Harpe and Nagnibeda. We construct explicit bases for the cut and flow spaces, interpret their coefficients topologically, and give sufficient conditions for them to be integral bases of the cut and flow lattices. Second, we determine the precise relationships between the discriminant groups of the cut and flow lattices and the higher critical and cocritical groups with error terms corresponding to torsion (co)homology. As an application, we generalize a result of Kotani and Sunada to give bounds for the complexity, girth, and connectivity of a complex in terms of Hermite's constant.Comment: 30 pages. Final version, to appear in Journal of Algebraic Combinatoric

Multilevel Deconstruction of the In Vivo Behavior of Looped DNA-Protein Complexes

Protein-DNA complexes with loops play a fundamental role in a wide variety of cellular processes, ranging from the regulation of DNA transcription to telomere maintenance. As ubiquitous as they are, their precise in vivo properties and their integration into the cellular function still remain largely unexplored. Here, we present a multilevel approach that efficiently connects in both directions molecular properties with cell physiology and use it to characterize the molecular properties of the looped DNA-lac repressor complex while functioning in vivo. The properties we uncover include the presence of two representative conformations of the complex, the stabilization of one conformation by DNA architectural proteins, and precise values of the underlying twisting elastic constants and bending free energies. Incorporation of all this molecular information into gene-regulation models reveals an unprecedented versatility of looped DNA-protein complexes at shaping the properties of gene expression.Comment: Open Access article available at http://www.plosone.org/article/fetchArticle.action?articleURI=info%3Adoi%2F10.1371%2Fjournal.pone.000035

Functional polymorphisms in the P2X7 receptor gene are associated with stress fracture injury

Context: Military recruits and elite athletes are susceptible to stress fracture injuries. Genetic predisposition has been postulated to have a role in their development. The P2X7 receptor (P2X7R) gene, a key regulator of bone remodelling, is a genetic candidate that may contribute to stress fracture predisposition. Objective: To evaluate the putative contribution of P2X7R to stress fracture injury in two separate cohorts, military personnel and elite athletes. Methods: In 210 Israeli Defence Forces (IDF) military conscripts, stress fracture injury was diagnosed (n=43) based on symptoms and a positive bone scan. In a separate cohort of 518 elite athletes, self-reported medical imaging scan-certified stress fracture injuries were recorded (n=125). Non-stress fracture controls were identified from these cohorts who had a normal bone scan or no history or symptoms of stress fracture injury. Study participants were genotyped for functional SNPs within the P2X7R gene using proprietary fluorescence-based competitive allele-specific PCR assay. Pearson Chi-square (χ2) tests, corrected for multiple comparisons, were used to assess associations in genotype frequencies. Results: The variant allele of P2X7R SNP rs3751143 (Glu496Ala- loss of function) was associated with stress fracture injury, while the variant allele of rs1718119 (Ala348Thr- gain of function) was associated with a reduced occurrence of stress fracture injury in military conscripts (P<0.05). The association of the variant allele of rs3751143 with stress fractures was replicated in elite athletes (P<0.05), whereas the variant allele of rs1718119 was also associated with reduced multiple stress fracture cases in elite athletes (P<0.05). Conclusions: The association between independent P2X7R polymorphisms with stress fracture prevalence supports the role of a genetic predisposition in the development of stress fracture injury

Once more on the Witten index of 3d supersymmetric YM-CS theory

The problem of counting the vacuum states in the supersymmetric 3d Yang-Mills-Chern-Simons theory is reconsidered. We resolve the controversy between its original calculation by Witten at large volumes and the calculation based on the evaluation of the effective Lagrangian in the small volume limit. We show that the latter calculation suffers from uncertainties associated with the singularities in the moduli space of classical vacua where the Born-Oppenheimer approximation breaks down. We also show that these singularities can be accurately treated in the Hamiltonian Born-Oppenheimer method, where one has to match carefully the effective wave functions on the Abelian valley and the wave functions of reduced non-Abelian QM theory near the singularities. This gives the same result as original Witten's calculation.Comment: 27 page

Effect of maternal Schistosoma mansoni infection and praziquantel treatment during pregnancy on Schistosoma mansoni infection and immune responsiveness among offspring at age five years.

INTRODUCTION: Offspring of Schistosoma mansoni-infected women in schistosomiasis-endemic areas may be sensitised in-utero. This may influence their immune responsiveness to schistosome infection and schistosomiasis-associated morbidity. Effects of praziquantel treatment of S. mansoni during pregnancy on risk of S. mansoni infection among offspring, and on their immune responsiveness when they become exposed to S. mansoni, are unknown. Here we examined effects of praziquantel treatment of S. mansoni during pregnancy on prevalence of S. mansoni and immune responsiveness among offspring at age five years. METHODS: In a trial in Uganda (ISRCTN32849447, http://www.controlled-trials.com/ISRCTN32849447/elliott), offspring of women treated with praziquantel or placebo during pregnancy were examined for S. mansoni infection and for cytokine and antibody responses to SWA and SEA, as well as for T cell expression of FoxP3, at age five years. RESULTS: Of the 1343 children examined, 32 (2.4%) had S. mansoni infection at age five years based on a single stool sample. Infection prevalence did not differ between children of treated or untreated mothers. Cytokine (IFNγ, IL-5, IL-10 and IL-13) and antibody (IgG1, Ig4 and IgE) responses to SWA and SEA, and FoxP3 expression, were higher among infected than uninfected children. Praziquantel treatment of S. mansoni during pregnancy had no effect on immune responses, with the exception of IL-10 responses to SWA, which was higher in offspring of women that received praziquantel during pregnancy than those who did not. CONCLUSION: We found no evidence that maternal S. mansoni infection and its treatment during pregnancy influence prevalence and intensity of S. mansoni infection or effector immune response to S. mansoni infection among offspring at age five years, but the observed effects on IL-10 responses to SWA suggest that maternal S. mansoni and its treatment during pregnancy may affect immunoregulatory responsiveness in childhood schistosomiasis. This might have implications for pathogenesis of the disease