The Likelihood Ratio Test and Full Bayesian Significance Test under small sample sizes for contingency tables

Hypothesis testing in contingency tables is usually based on asymptotic results, thereby restricting its proper use to large samples. To study these tests in small samples, we consider the likelihood ratio test and define an accurate index, the P-value, for the celebrated hypotheses of homogeneity, independence, and Hardy-Weinberg equilibrium. The aim is to understand the use of the asymptotic results of the frequentist Likelihood Ratio Test and the Bayesian FBST -- Full Bayesian Significance Test -- under small-sample scenarios. The proposed exact P-value is used as a benchmark to understand the other indices. We perform analysis in different scenarios, considering different sample sizes and different table dimensions. The exact Fisher test for $2 \times 2$ tables that drastically reduces the sample space is also discussed. The main message of this paper is that all indices have very similar behavior, so the tests based on asymptotic results are very good to be used in any circumstance, even with small sample sizes

Unbiased Risk Estimation in the Normal Means Problem via Coupled Bootstrap Techniques

We study a new method for estimating the risk of an arbitrary estimator of the mean vector in the classical normal means problem. The key idea is to generate two auxiliary data vectors, by adding two carefully constructed normal noise vectors to the original data vector. We then train the estimator of interest on the first auxiliary data vector and test it on the second. In order to stabilize the estimate of risk, we average this procedure over multiple draws of the synthetic noise. A key aspect of this coupled bootstrap approach is that it delivers an unbiased estimate of risk under no assumptions on the estimator of the mean vector, albeit for a slightly "harder" version of the original normal means problem, where the noise variance is inflated. We show that, under the assumptions required for Stein's unbiased risk estimator (SURE), a limiting version of the coupled bootstrap estimator recovers SURE exactly (with an infinitesimal auxiliary noise variance and infinite bootstrap samples). We also analyze a bias-variance decomposition of the error of our risk estimator, to elucidate the effects of the variance of the auxiliary noise and the number of bootstrap samples on the accuracy of the risk estimator. Lastly, we demonstrate that our coupled bootstrap risk estimator performs quite favorably in simulated experiments and in an image denoising example.Comment: 29 pages, 8 figure

Unbiased Test Error Estimation in the Poisson Means Problem via Coupled Bootstrap Techniques

We propose a coupled bootstrap estimator for the test error of an arbitrary algorithm that estimates the mean in a Poisson sequence, often called the Poisson means problem. The idea behind our method is to generate two carefully-designed data vectors from the original data vector, by using synthetic binomial noise. One such vector acts as the training sample and the second acts as the test sample. To stabilize the test error estimate, we average this over multiple draws of the synthetic noise. A key property of our coupled bootstrap estimator is that it is unbiased for the test error in a problem where the original mean has been shrunken by a small factor, driven by the success probability $p$ in the binomial noise. Further, in the limit as $p \to 0$, we show that the proposed estimator recovers a known unbiased estimator for the test error, under no assumptions on the algorithm at hand (in particular, no smoothness assumptions). Our methodology applies to two central loss functions that can be used to a test error metric: Poisson deviance and squared loss. Through a bias-variance decomposition, for each loss function, we analyze the effects of the binomial success probability and the number of bootstrap samples and on the accuracy of the estimator. We also investigate our method empirically across a variety of settings, using simulated as well as real data.Comment: 26 pages, 9 figure

Assessment of data on vector and host competence for Japanese encephalitis virus: A systematic review update of Oliveira et al. 2018

Japanese Encephalitis (JE) is an emerging, zoonotic disease transmitted primarily by Culex species mosquitoes (particularly Culex tritaeniorhynchus) carrying the flavivirus Japanese encephalitis virus (JEV). Japanese encephalitis virus maintains its life cycle between mosquitoes and vertebrate hosts, primarily pigs and wading birds (Le Flohic et al., 2013). JE is an untreatable and incurable disease that, in humans, can result in inflammation of the brain (encephalitis) causing fever, headache, respiratory signs, gastrointestinal signs, confusion, seizures, coma, and, in some cases, death (Fischer et al., 2012; Kliegman et al., 2015). The United States (US) is considered a susceptible region with great potential for JEV introduction, given the availability of competent insect vectors, susceptible maintenance (avian) hosts, large populations of susceptible, amplifying hosts (domestic and feral pigs), intensive travel and trade activities to and from JEV-affected countries, and areas with similar climatic and environmental conditions to countries where the virus is epidemic. To investigate the risk of JEV introduction and establishment, Oliveira and colleagues performed a risk assessment (Oliveira et al., 2019) supported by a systematic review of vector and host competency for JEV (Oliveira et al., 2018). 3Although Oliveira et al. (2019) found the risk of introduction of JEV in the US through entry of infected mosquitoes via airplanes to be very high, the risk of establishment was considered negligible; yet, increases in international trade and globalization, as well as changes in climate and land use, and the recent incursion of a new JEV genotype into areas previously free from disease, as observed in Australia with the invasion and expansion of JEV (Genotype IV) in the eastern and southeastern states, warrants the need for an update of the review and risk assessment. The objective of this review is to update the systematic review (Oliveira et al., 2018) on host and vector competence of transmission of the Japanese encephalitis virus

Identification of Critical Amino Acids in the IgE Epitopes of Ric c 1 and Ric c 3 and the Application of Glutamic Acid as an IgE Blocker

Background: The allergenicity of Ricinus communis L. (castor bean, Euphorbiaceae) is associated with components of its seeds and pollen. Castor bean allergy has been described not only in laboratory workers, but also in personnel working in oil processing mills, fertilizer retail, the upholstery industry and other industrial fields. In the present study, we describe the critical amino acids in the IgE-binding epitopes in Ric c 1 and Ric c 3, two major allergens of R. communis. In addition, we also investigate the cross-reactivity between castor bean and some air and food allergen extracts commonly used in allergy diagnosis. Methodology/Principal Findings: The IgE reactivity of human sera from atopic patients was screened by immune-dot blot against castor bean allergens. Allergenic activity was evaluated in vitro using a rat mast cell activation assay and by ELISA. Cross-reactivity was observed between castor bean allergens and extracts from shrimp, fish, gluten, wheat, soybean, peanut, corn, house dust, tobacco and airborne fungal allergens. We observed that treatment of rat and human sera (from atopic patients) with glutamic acid reduced the IgE-epitope interaction. Conclusions/Significance: The identification of glutamic acid residues with critical roles in IgE-binding to Ric c 3 and Ric c

Angiotensin-(1–7)/Mas axis integrity is required for the expression of object recognition memory

AbstractIt has been shown that the brain has its own intrinsic renin–angiotensin system (RAS) and angiotensin-(1–7) (Ang-(1–7)) is particularly interesting, because it appears to counterbalance most of the Ang II effects. Ang-(1–7) exerts its biological function through activation of the G-protein-coupled receptor Mas. Interestingly, hippocampus is one of the regions with higher expression of Mas. However, the role of Ang-(1–7)/Mas axis in hippocampus-dependent memories is still poorly understood. Here we demonstrated that Mas ablation, as well as the blockade of Mas in the CA1-hippocampus, impaired object recognition memory (ORM). We also demonstrated that the blockade of Ang II receptors AT1, but not AT2, recovers ORM impairment of Mas-deficient mice. Considering that high concentrations of Ang-(1–7) may activate AT1 receptors, nonspecifically, we evaluate the levels of Ang-(1–7) and its main precursors Ang I and Ang II in the hippocampus of Mas-deficient mice. The Ang I and Ang II levels are unaltered in the whole hipocampus of MasKo. However, Ang-(1–7) concentration is increased in the whole hippocampus of MasKo mice, as well as in the CA1 area. Taken together, our findings suggest that the functionality of the Ang-(1–7)/Mas axis is essential for normal ORM processing

Revisiting the role of swine on the risk of Japanese Encephalitis Virus (JEV) transmission in the United States: a rapid systematic review of the literature

Japanese Encephalitis (JE) is an emerging, zoonotic disease transmitted primarily by Culex species mosquitoes (particularly Culex tritaeniorhynchus) carrying the flavivirus Japanese encephalitis virus (JEV). Japanese encephalitis virus maintains its life cycle between mosquitoes and vertebrate hosts, primarily pigs and wading birds (Le Flohic et al., 2013). In humans, JEV infection causes inflammation of the brain (encephalitis) that can cause fever, headache, respiratory distress, gastrointestinal pain, confusion, seizures, and, in some cases, death (Fischer et al., 2012; Hills et al., 2014). The global incidence of JE is uncertain. Effectivity and quality of JE surveillance in endemic countries vary (Jayatilleke et al. 2020), as does availability of diagnostic testing throughout the world. In 2006, the WHO published a position paper on JE vaccines reporting an annual estimation of at least 50,000 new JE cases among those living in countries considered endemic. Campbell et al. (2011) updated prior estimations and predicted a global incidence of JE cases to be nearly 67,900 per year. Most recently, Quan et al. (2020) reported a global estimation of JE incidence of approximately 100,000 per year. Among all clinical cases, children under the age of 10 comprise the majority affected (WHO, 2006). Whereas less than 1% of the cases are accompanied by symptoms, 30% of the symptomatic cases are fatal (Campbell et al., 2011). Furthermore, JE is an untreatable and incurable disease that, once introduced in a community, can lead to devastating economic and health impacts. The United States (US) is considered a susceptible region with great potential for JEV introduction. The availability of competent vectors, susceptible maintenance hosts (avian), intensive travel and trade activities to and from JEV-affected countries, areas with similar climatic and environmental conditions to countries where the virus is epidemic, and large populations of susceptible, amplifying hosts (domestic and feral pigs), makes the US the perfect next-stop in the JEV travel itinerary. In fact, the US is the world’s third-largest producer and consumer of pork and pork products (USDA - ERS). The size of the swine industry in the US can not only be positively correlated with the ability of this virus to invade and establish itself, but also to the impact that an incursion would cause to the economy and the populations’ health. As pigs are considered the main amplifying host of JEV, an extensive review of the literature and identification of knowledge gaps may guide researchers, stakeholders, and policy makers on effort prioritization, development of precautionary intervention measures (to prevent JEV introduction), and evaluation of disease control measures (in case of JEV incursion). Although current conditions have not been favorable for JEV to establish in the US, increases in international trade and globalization, as well as changes in climate and land use, and reductions in pesticide use, can contribute to its rapid and wide geographical spread (Oliveira et al., 2018). A good understanding of the role of swine as an amplifying host for this virus is critical to public health authorities when planning and executing interventions to control the spread of JEV. Therefore, our objectives are 1) to investigate the role of swine on the risk of JEV transmission in the US as an effort for preparedness in the case of an introduction, and 2) to identify knowledge gaps that may serve as a guide to future research efforts

Mapping mania symptoms based on focal brain damage

BACKGROUND. Although mania is characteristic of bipolar disorder, it can also occur following focal brain damage. Such cases may provide unique insight into brain regions responsible for mania symptoms and identify therapeutic targets. METHODS. Lesion locations associated with mania were identified using a systematic literature search (n = 41) and mapped onto a common brain atlas. The network of brain regions functionally connected to each lesion location was computed using normative human connectome data (resting-state functional MRI, n = 1000) and contrasted with those obtained from lesion locations not associated with mania (n = 79). Reproducibility was assessed using independent cohorts of mania lesions derived from clinical chart review (n = 15) and of control lesions (n = 490). Results were compared with brain stimulation sites previously reported to induce or relieve mania symptoms. RESULTS. Lesion locations associated with mania were heterogeneous and no single brain region was lesioned in all, or even most, cases. However, these lesion locations showed a unique pattern of functional connectivity to the right orbitofrontal cortex, right inferior temporal gyrus, and right frontal pole. This connectivity profile was reproducible across independent lesion cohorts and aligned with the effects of therapeutic brain stimulation on mania symptoms. CONCLUSION. Brain lesions associated with mania are characterized by a specific pattern of brain connectivity that lends insight into localization of mania symptoms and potential therapeutic targets. FUNDING. Fundação para a Ciência e Tecnologia (FCT), Harvard Medical School DuPont-Warren Fellowship, Portuguese national funds from FCT and Fundo Europeu de Desenvolvimento Regional, Child Neurology Foundation Shields Research, Sidney R. Baer, Jr. Foundation, Nancy Lurie Marks Foundation, Mather's Foundation, and the NIH.publishersversionpublishe

Recurrent Pregnancy Loss: Investigations and Interventions

Recurrent pregnancy loss (RPL) affects 0.8–1.4% of couples, and this prevalence increases with aging. However, etiology is commonly unknown, and most therapies are not supported by strong evidence. There are many examinations that investigate causes of RPL: hormonal status, spermatozoa morphology and DNA fragmentation, immunologic status, uterine assessment, thrombophilia, and others. Recently different types of treatment have emerged, most lacking good evidence. As for example, we may mention the use of anticoagulants, aspirin, corticosteroids, progesterone, and antioxidants and psychological support. It is argued that some procedures such as preimplantation genetic testing for aneuploidy and intracytoplasmic morphologically selected sperm injection would impact on the outcomes and help RPL management. This chapter will discuss the current evidence concerning examinations and treatments that would improve the outcomes in patients with RPL, with recommended practice