Frequentist rules for regulatory approval of subgroups in phase III trials: A fresh look at an old problem.

BACKGROUND: The number of Phase III trials that include a biomarker in design and analysis has increased due to interest in personalised medicine. For genetic mutations and other predictive biomarkers, the trial sample comprises two subgroups, one of which, say B+ is known or suspected to achieve a larger treatment effect than the other B-. Despite treatment effect heterogeneity, trials often draw patients from both subgroups, since the lower responding B- subgroup may also gain benefit from the intervention. In this case, regulators/commissioners must decide what constitutes sufficient evidence to approve the drug in the B- population. METHODS AND RESULTS: Assuming trial analysis can be completed using generalised linear models, we define and evaluate three frequentist decision rules for approval. For rule one, the significance of the average treatment effect in B- should exceed a pre-defined minimum value, say ZB->L. For rule two, the data from the low-responding group B- should increase statistical significance. For rule three, the subgroup-treatment interaction should be non-significant, using type I error chosen to ensure that estimated difference between the two subgroup effects is acceptable. Rules are evaluated based on conditional power, given that there is an overall significant treatment effect. We show how different rules perform according to the distribution of patients across the two subgroups and when analyses include additional (stratification) covariates in the analysis, thereby conferring correlation between subgroup effects. CONCLUSIONS: When additional conditions are required for approval of a new treatment in a lower response subgroup, easily applied rules based on minimum effect sizes and relaxed interaction tests are available. Choice of rule is influenced by the proportion of patients sampled from the two subgroups but less so by the correlation between subgroup effects

The novel mu-opioid antagonist, GSK1521498, reduces ethanol consumption in C57BL/6J mice.

RATIONALE Using the drinking-in-the-dark (DID) model, we compared the effects of a novel mu-opioid receptor antagonist, GSK1521498, with naltrexone, a licensed treatment of alcohol dependence, on ethanol consumption in mice. OBJECTIVE We test the ability of GSK1521498 to reduce alcohol consumption and compare its intrinsic efficacy to that of naltrexone by comparing the two drugs at doses matched for equivalent receptor occupancy. METHODS Thirty-six C57BL/6J mice were tested in a DID procedure. In 2-day cycles, animals experienced one baseline, injection-free session, and one test session when they received two injections, one of test drug and one placebo. All animals received GSK1521498 (0, 0.1, 1 and 3 mg/kg, i.p., 30 min pre-treatment) and naltrexone (0, 0.1, 1 and 3 mg/kg, s.c. 10 min pre-treatment) in a cross-over design. Receptor occupancies following the same doses were determined ex vivo in separate groups by autoradiography, using [3H]DAMGO. Binding in the region of interest was measured integrally by computer-assisted microdensitometry and corrected for non-specific binding. RESULTS Both GSK1521498 and naltrexone dose-dependently decreased ethanol consumption. When drug doses were matched for 70-75 % receptor occupancy, GSK1521498 3 mg/kg, i.p., caused a 2.5-fold greater reduction in alcohol consumption than naltrexone 0.1 mg/kg, s.c. Both GSK1521498 and naltrexone significantly reduced sucrose consumption at a dose of 1 mg/kg but not 0.1 mg/kg. In a test of conditioned taste aversion, GSK1521498 (3 mg/kg) reduced sucrose consumption 24 h following exposure to a conditioning injection. CONCLUSIONS Both opioid receptor antagonists reduced alcohol consumption but GK1521498 has higher intrinsic efficacy than naltrexone

Sex differences in the association between plasma copeptin and incident type 2 diabetes: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study

AIMS/HYPOTHESIS: Vasopressin plays a role in osmoregulation, glucose homeostasis and inflammation. Therefore, plasma copeptin, the stable C-terminal portion of the precursor of vasopressin, has strong potential as a biomarker for the cardiometabolic syndrome and diabetes. Previous results were contradictory, which may be explained by differences between men and women in responsiveness of the vasopressin system. The aim of this study was to evaluate the usefulness of copeptin for prediction of future type 2 diabetes in men and women separately. METHODS: From the Prevention of Renal and Vascular Endstage Disease (PREVEND) study, 4,063 women and 3,909 men without diabetes at baseline were included. A total of 208 women and 288 men developed diabetes during a median follow-up of 7.7 years. RESULTS: In multivariable-adjusted models, we observed a stronger association of copeptin with risk of future diabetes in women (OR 1.49 [95% CI 1.24, 1.79]) than in men (OR 1.01 [95% CI 0.85, 1.19]) (p (interaction) < 0.01). The addition of copeptin to the Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) clinical model improved the discriminative value (C-statistic,+0.007, p = 0.02) and reclassification (integrated discrimination improvement [IDI] = 0.004, p < 0.01) in women. However, we observed no improvement in men. The additive value of copeptin in women was maintained when other independent predictors, such as glucose, high sensitivity C-reactive protein (hs-CRP) and 24 h urinary albumin excretion (UAE), were included in the model. CONCLUSIONS/INTERPRETATION: The association of plasma copeptin with the risk of developing diabetes was stronger in women than in men. Plasma copeptin alone, and along with existing biomarkers (glucose, hs-CRP and UAE), significantly improved the risk prediction for diabetes in women

On dynamic network entropy in cancer

The cellular phenotype is described by a complex network of molecular interactions. Elucidating network properties that distinguish disease from the healthy cellular state is therefore of critical importance for gaining systems-level insights into disease mechanisms and ultimately for developing improved therapies. By integrating gene expression data with a protein interaction network to induce a stochastic dynamics on the network, we here demonstrate that cancer cells are characterised by an increase in the dynamic network entropy, compared to cells of normal physiology. Using a fundamental relation between the macroscopic resilience of a dynamical system and the uncertainty (entropy) in the underlying microscopic processes, we argue that cancer cells will be more robust to random gene perturbations. In addition, we formally demonstrate that gene expression differences between normal and cancer tissue are anticorrelated with local dynamic entropy changes, thus providing a systemic link between gene expression changes at the nodes and their local network dynamics. In particular, we also find that genes which drive cell-proliferation in cancer cells and which often encode oncogenes are associated with reductions in the dynamic network entropy. In summary, our results support the view that the observed increased robustness of cancer cells to perturbation and therapy may be due to an increase in the dynamic network entropy that allows cells to adapt to the new cellular stresses. Conversely, genes that exhibit local flux entropy decreases in cancer may render cancer cells more susceptible to targeted intervention and may therefore represent promising drug targets.Comment: 10 pages, 3 figures, 4 tables. Submitte

The social production of substance abuse and HIV/HCV risk: an exploratory study of opioid-using immigrants from the former Soviet Union living in New York City

<p>Abstract</p> <p>Background</p> <p>Several former Soviet countries have witnessed the rapid emergence of major epidemics of injection drug use (IDU) and associated HIV/HCV, suggesting that immigrants from the former Soviet Union (FSU) may be at heightened risk for similar problems. This exploratory study examines substance use patterns among the understudied population of opioid-using FSU immigrants in the U.S., as well as social contextual factors that may increase these immigrants' susceptibility to opioid abuse and HIV/HCV infection.</p> <p>Methods</p> <p>In-depth interviews were conducted with 10 FSU immigrants living in New York City who initiated opioid use in adolescence or young adulthood, and with 6 drug treatment providers working with this population. Informed by a grounded theory approach, interview transcripts were inductively coded and analyzed to identify key themes.</p> <p>Results</p> <p>The "trauma" of the immigration/acculturation experience was emphasized by participants as playing a critical role in motivating opioid use. Interview data suggest that substance use patterns formed in the high-risk environment of the FSU may persist as behavioral norms within New York City FSU immigrant communities - including a predilection for heroin use among youth, a high prevalence of injection, and a tolerance for syringe sharing within substance-using peer networks. Multiple levels of social context may reproduce FSU immigrants' vulnerability to substance abuse and disease such as: peer-based interactional contexts in which participants typically used opioids; community workplace settings in which some participants were introduced to and obtained opioids; and cultural norms, with roots in Soviet-era social policies, stigmatizing substance abuse which may contribute to immigrants' reluctance to seek disease prevention and drug treatment services.</p> <p>Conclusion</p> <p>Several behavioral and contextual factors appear to increase FSU immigrants' risk for opioid abuse, IDU and infectious disease. Further research on opioid-using FSU immigrants is warranted and may help prevent increases in HIV/HCV prevalence from occurring within these communities.</p

MuSR method and tomographic probability representation of spin states

Muon spin rotation/relaxation/resonance (MuSR) technique for studying matter structures is considered by means of a recently introduced probability representation of quantum spin states. A relation between experimental MuSR histograms and muon spin tomograms is established. Time evolution of muonium, anomalous muonium, and a muonium-like system is studied in the tomographic representation. Entanglement phenomenon of a bipartite muon-electron system is investigated via tomographic analogues of Bell number and positive partial transpose (PPT) criterion. Reconstruction of the muon-electron spin state as well as the total spin tomography of composed system is discussed.Comment: 20 pages, 4 figures, LaTeX, submitted to Journal of Russian Laser Researc

Guillain-Barré syndrome: a century of progress

In 1916, Guillain, Barré and Strohl reported on two cases of acute flaccid paralysis with high cerebrospinal fluid protein levels and normal cell counts — novel findings that identified the disease we now know as Guillain–Barré syndrome (GBS). 100 years on, we have made great progress with the clinical and pathological characterization of GBS. Early clinicopathological and animal studies indicated that GBS was an immune-mediated demyelinating disorder, and that severe GBS could result in secondary axonal injury; the current treatments of plasma exchange and intravenous immunoglobulin, which were developed in the 1980s, are based on this premise. Subsequent work has, however, shown that primary axonal injury can be the underlying disease. The association of Campylobacter jejuni strains has led to confirmation that anti-ganglioside antibodies are pathogenic and that axonal GBS involves an antibody and complement-mediated disruption of nodes of Ranvier, neuromuscular junctions and other neuronal and glial membranes. Now, ongoing clinical trials of the complement inhibitor eculizumab are the first targeted immunotherapy in GBS

Biophysical and electrochemical studies of protein-nucleic acid interactions

This review is devoted to biophysical and electrochemical methods used for studying protein-nucleic acid (NA) interactions. The importance of NA structure and protein-NA recognition for essential cellular processes, such as replication or transcription, is discussed to provide background for description of a range of biophysical chemistry methods that are applied to study a wide scope of protein-DNA and protein-RNA complexes. These techniques employ different detection principles with specific advantages and limitations and are often combined as mutually complementary approaches to provide a complete description of the interactions. Electrochemical methods have proven to be of great utility in such studies because they provide sensitive measurements and can be combined with other approaches that facilitate the protein-NA interactions. Recent applications of electrochemical methods in studies of protein-NA interactions are discussed in detail

Judging the difference between attractiveness and health: does exposure to model images influence the judgments made by men and women?

Recent research has shown facial adiposity (apparent weight in the face) to be a significant predictor of both attractiveness and health, thus making it an important determinant of mate selection. Studies looking at the relationship between attractiveness and health have shown that individuals differentiate between the two by preferring a lower weight for attractiveness than for health in female faces. However, these studies have either been correlational studies, or have investigated weight perceived from only the face. These differences have been discussed with regard to sociocultural factors such as pressure from parents, peers and also media, which has been seen to have the highest influence. While exposure to media images has been shown to influence women’s own body image, no study has yet directly tested the influence of these factors on people’s preferred weight in other women’s bodies. Here we examine how a short exposure to images of models influences men’s and women’s judgments of the most healthy looking and attractive BMI in Malaysian Chinese women’s bodies by comparing differences in preferences (for attractiveness and health) between groups exposed to images of models of varying attractiveness and body weight. Results indicated that participants preferred a lower weight for attractiveness than for health. Further, women’s but not men’s preferred BMI for attractiveness, but not health, was influenced by the type of media images to which they were exposed, suggesting that short term exposure to model images affect women’s perceptions of attractiveness but not health