Comparison of Bayesian and frequentist group-sequential clinical trial designs

Background: There is a growing interest in the use of Bayesian adaptive designs in late-phase clinical trials. This includes the use of stopping rules based on Bayesian analyses in which the frequentist type I error rate is controlled as in frequentist group-sequential designs. Methods: This paper presents a practical comparison of Bayesian and frequentist group-sequential tests. Focussing on the setting in which data can be summarised by normally distributed test statistics, we evaluate and compare boundary values and operating characteristics. Results: Although Bayesian and frequentist group-sequential approaches are based on fundamentally different paradigms, in a single arm trial or two-arm comparative trial with a prior distribution specified for the treatment difference, Bayesian and frequentist group-sequential tests can have identical stopping rules if particular critical values with which the posterior probability is compared or particular spending function values are chosen. If the Bayesian critical values at different looks are restricted to be equal, O’Brien and Fleming’s design corresponds to a Bayesian design with an exceptionally informative negative prior, Pocock’s design to a Bayesian design with a non-informative prior and frequentist designs with a linear alpha spending function are very similar to Bayesian designs with slightly informative priors. This contrasts with the setting of a comparative trial with independent prior distributions specified for treatment effects in different groups. In this case Bayesian and frequentist group-sequential tests cannot have the same stopping rule as the Bayesian stopping rule depends on the observed means in the two groups and not just on their difference. In this setting the Bayesian test can only be guaranteed to control the type I error for a specified range of values of the control group treatment effect. Conclusions: Comparison of frequentist and Bayesian designs can encourage careful thought about design parameters and help to ensure appropriate design choices are made

Site-specific identification and quantitation of endogenous SUMO modifications under native conditions.

Small ubiquitin-like modifier (SUMO) modification regulates numerous cellular processes. Unlike ubiquitin, detection of endogenous SUMOylated proteins is limited by the lack of naturally occurring protease sites in the C-terminal tail of SUMO proteins. Proteome-wide detection of SUMOylation sites on target proteins typically requires ectopic expression of mutant SUMOs with introduced tryptic sites. Here, we report a method for proteome-wide, site-level detection of endogenous SUMOylation that uses α-lytic protease, WaLP. WaLP digestion of SUMOylated proteins generates peptides containing SUMO-remnant diglycyl-lysine (KGG) at the site of SUMO modification. Using previously developed immuno-affinity isolation of KGG-containing peptides followed by mass spectrometry, we identified 1209 unique endogenous SUMO modification sites. We also demonstrate the impact of proteasome inhibition on ubiquitin and SUMO-modified proteomes using parallel quantitation of ubiquitylated and SUMOylated peptides. This methodological advancement enables determination of endogenous SUMOylated proteins under completely native conditions

Mentoring the Mentors: Implementation and Evaluation of Four Fogarty-Sponsored Mentoring Training Workshops in Low-and Middle-Income Countries.

A growing body of evidence highlights the importance of competent mentoring in academic research. We describe the development, implementation, and evaluation of four regional 2-day intensive workshops to train mid- and senior-level investigators conducting public health, clinical, and basic science research across multiple academic institutions in low- and middle-income countries (LMICs) on tools and techniques of effective mentoring. Sponsored by the Fogarty International Center, workshops included didactic presentations, interactive discussions, and small-group problem-based learning and were conducted in Lima, Peru; Mombasa, Kenya; Bangalore, India; and Johannesburg, South Africa, from 2013 to 2016. Mid- or senior-level faculty from multiple academic institutions within each region applied and were selected. Thirty faculty from 12 South America-based institutions, 29 faculty from eight East Africa-based institutions, 37 faculty from 14 South Asia-based institutions, and 36 faculty from 13 Africa-based institutions participated, with diverse representation across disciplines, gender, and academic rank. Discussions and evaluations revealed important comparisons and contrasts in the practice of mentoring, and specific barriers and facilitators to mentoring within each cultural and regional context. Specific regional issues related to hierarchy, the post-colonial legacy, and diversity arose as challenges to mentoring in different parts of the world. Common barriers included a lack of a culture of mentoring, time constraints, lack of formal training, and a lack of recognition for mentoring. These workshops provided valuable training, were among the first of their kind, were well-attended, rated highly, and provided concepts and a structure for the development and strengthening of formal mentoring programs across LMIC institutions

Evaluation of Iron Deficiency Anemia in a Pediatric Clinic in the Dominican Republic

BackgroundIron deficiency and iron deficiency anemia affect billions of people worldwide. Infants and young children are the most vulnerable. The Niños Primeros en Salud pediatric clinic aims to follow the American Academy of Pediatrics (AAP) recommendation to screen all children at 12 months of age, a vital period for development and the time of greatest risk.ObjectivesTo evaluate the clinic's performance screening for, diagnosing, and treating iron deficiency anemia; and to describe the prevalence and severity of anemia in infants and children attending a perirural clinic in the Dominican Republic.MethodsA total of 293 charts were reviewed for hemoglobin tests performed between 9 and 15 months of age. If a hemoglobin screening was performed, then sociodemographic characteristics, medical history, and laboratory data were collected. If blood tests revealed anemia, then the presence or absence of documented anemia diagnosis as well as the presence or absence of documented provision of iron therapy were recorded.FindingsLess than one-third (87, 29.7%) of patients had a documented hemoglobin test performed in this age range. Of these, 89.6% indicated anemia and nearly half (48.6%) revealed moderate anemia. One-third (34%) of hemoglobin results revealing anemia were not accompanied by a documented diagnosis. The vast majority (86.5%) of results indicated microcytosis, yet just more than half (50.8%) of anemic patients received iron therapy.ConclusionsMany children at the clinic were not screened for iron deficiency anemia during the period of highest risk. In the participants screened, iron deficiency anemia was underdiagnosed and often untreated. Anemia is a significant burden in this community—one demanding reliable screening and universal supplementation

Crab in Amber Reveals an Early Colonization of Nonmarine Environments During the Cretaceous

Amber fossils provide snapshots of the anatomy, biology, and ecology of extinct organisms that are otherwise inaccessible. The best-known fossils in amber are terrestrial arthropods—principally insects—whereas aquatic organisms are rarely represented. Here, we present the first record of true crabs (Brachyura) in amber—from the Cretaceous of Myanmar [~100 to 99 million years (Ma)]. The new fossil preserves large compound eyes, delicate mouthparts, and even gills. This modern-looking crab is nested within crown Eubrachyura, or “higher” true crabs, which includes the majority of brachyuran species living today. The fossil appears to have been trapped in a brackish or freshwater setting near a coastal to fluvio-estuarine environment, bridging the gap between the predicted molecular divergence of nonmarine crabs (~130 Ma) and their younger fossil record (latest Cretaceous and Paleogene, ~75 to 50 Ma) while providing a reliable calibration point for molecular divergence time estimates for higher crown eubrachyurans

Intellectual Property and Public Health – A White Paper

On October 26, 2012, the University of Akron School of Law’s Center for Intellectual Property and Technology hosted its Sixth Annual IP Scholars Forum. In attendance were thirteen legal scholars with expertise and an interest in IP and public health who met to discuss problems and potential solutions at the intersection of these fields. This report summarizes this discussion by describing the problems raised, areas of agreement and disagreement between the participants, suggestions and solutions made by participants and the subsequent evaluations of these suggestions and solutions. Led by the moderator, participants at the Forum focused generally on three broad questions. First, are there alternatives to either the patent system or specific patent doctrines that can provide or help provide sufficient incentives for health-related innovation? Second, is health information being used proprietarily and if so, is this type of protection appropriate? Third, does IP conflict with other non-IP values that are important in health and how does or can IP law help resolve these conflicts? This report addresses each of these questions in turn