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Model Assessment
Published in Gary L. Rosner, Purushottam W. Laud, Wesley O. Johnson, Bayesian Thinking in Biostatistics, 2021
Gary L. Rosner, Purushottam W. Laud, Wesley O. Johnson
On the other hand, in the case of a point null hypothesis, like , or , the above description requires modification as . We must, then, specify a prior probability that reflects our belief that the null hypothesis is true. If H0 is a simple hypothesis, so that contains a single point, then it completely specifies the sampling distribution for the data. In this case, we can specify the prior under the alternative H1 as for all . This works since . If, however, H0 is not a simple hypothesis, such as , further modifications are required. We will not consider such hypotheses in this book but instead recommend the excellent treatment by Berger and co-authors [29, 31, 32, 92] to interested readers.
The Bioenergetics of Mammalian Sperm Motility
Published in Claude Gagnon, Controls of Sperm Motility, 2020
The immediate source of energy for motility is the hydrolysis of ATP catalyzed by dynein ATPase which drives the sliding of adjacent microtubules.3 ATP is regenerated by the breakdown of sugars (principally glucose or fructose) to lactate by the glycolytic pathway and the mitochondrial oxidation of substrates through the citric acid cycle (Figure 1).3-5 ATP in the sperm cell turns over rapidly e.g., in boar sperm, the concentration of ATP is about 20 nmol/108 spermatozoa and about half of this is metabolized each minute because the rate of the mitochondrial respiration of endogenous substrates is equivalent to 8 nmol ATP/min/108 sperm.6 The close integration of energy metabolism with energy consumption is therefore essential and one way this might be achieved is by a negative feedback of ATP and related factors to inhibit ATP production countered by a positive feedback of ADP or related factors to stimulate it. We shall examine how far this simple hypothesis can account for published experimental observations. Other effectors (E) can act on the flagellar apparatus or directly on the metabolic pathways (Figure 1).
Bayes Factor–Based Test Statistics
Published in Albert Vexler, Alan D. Hutson, Xiwei Chen, Statistical Testing Strategies in the Health Sciences, 2017
Albert Vexler, Alan D. Hutson, Xiwei Chen
As an introduction to the Bayesian approach as it contrasts to frequentist methods, first consider the simple hypothesis test H0: θ = θ0 versus H1: θ = θ1, where the parameters θ0 and θ1 are known. Given an observed random sample X = {x1,…, xn}, we can then construct the likelihood ratio test statistic L = f(X|θ1)/f(X|θ0) for the purpose of determining which hypothesis is more probable, when f denotes a density function of X. The decision-making procedure is to reject H0 for large values of L. In this case, the decision-making rule based on the likelihood ratio test is uniformly most powerful. See the appendix and Section 4.2 for details. Although this classical hypothesis testing approach has a long and celebrated history in the statistical literature and continues to be a favorite of practitioners, it can be applied in a straightforward manner only in the case of a simple hypothesis; that is, the parameter under the alternative hypothesis, θ1, is known.
Predictive tools to determine risk of infection in kidney transplant recipients
Published in Expert Review of Anti-infective Therapy, 2020
Mario Fernández-Ruiz, Francisco López-Medrano, José María Aguado
The use of viral replication kinetics as a surrogate for immunosuppression is founded on a simple hypothesis. Human virome is composed of a staggering diversity of single- and double-stranded RNA and DNA viruses that infect the human being at multiple anatomical sites. These viral communities establish a complex, bidirectional interplay with components of host immunity that goes beyond the traditional paradigm of host-pathogen interaction [95]. Replication of commensal and opportunistic viruses exert a detrimental impact on the immune function leading to allograft rejection or predisposing to opportunistic infections, whereas no pathogenic effect has been demonstrated for the so-called ‘orphan viruses’. Moreover, some viruses may even have a beneficial immunomodulatory role [96]. The expansion of human virome is tightly controlled by the innate and, to a greater extent, adaptive arms of immune system. Plasma or blood loads of highly prevalent viruses reflect a dynamic steady state between virus replication and host’s response in non-immunocompromised individuals, often based on a high daily turnover rate. Immunosuppressive therapy may alter this balance, resulting in increasing or persistent replication, as also observed for other immunocompromised hosts. The net state of immunosuppression would be inferred from viral kinetics, with high and low viral loads suggesting an increased risk of post-transplant infection and graft rejection, respectively.
Plecanatide for the treatment of chronic idiopathic constipation in adult patients
Published in Expert Review of Clinical Pharmacology, 2019
Gabrio Bassotti, Paolo Usai Satta, Massimo Bellini
The term CIC defines a semantic umbrella including different conditions, such as normal transit constipation, slow transit constipation and functional defecation disorders. Thus, understanding the efficacy and the potential role of newer pharmacological agents, such as lubiprostone, linaclotide, plecanatide, velusetrag, and prucalopride, remains quite difficult and our informations is largely influenced by the different kind of patients enrolled in the different studies. This is probably one of the reasons why, according to the recently published paper by Pritchard and Barucha et al [45], ‘old’ laxatives, such as bulking agents, polyethylene glycol and bisacodyl, have a more favorable NNT in comparison with the above mentioned newer agents. However, some points deserve to be stressed. First, the studies used to detect the NNT for the different drugs enrolled different number of patients with different end points. Generally speaking, the studies using ‘old’ laxatives recruited a lower number of patients and required less strict criteria for the enrollment and for labeling the patients as responders. Secondly, the ‘old’ laxatives are available at lower costs, so it could be possible that the trials with newer agents had enrolled a good portion of more severely constipated patients, refractory to traditional laxatives. However, because the lack of response to traditional laxatives was not an entry criterion for the studies carried out using plecanatide, linaclotide and lubiprostone, this remains only a simple hypothesis.
New insights into IFN-γ in rheumatoid arthritis: role in the era of JAK inhibitors
Published in Immunological Medicine, 2020
IFN-γ interacts with its receptor to trigger cellular responses. The IFN-γ receptor consists of two transmembrane chains, IFN-γR1 and IFN-γR2, both of which are required for IFN-γ signaling. Deficiency in IFN-γR1 and that in IFN-γR2 are both associated with mendelian susceptibility to mycobacterial disease [10]. After ligand-receptor binding, two members of JAK, JAK1 and JAK2, interact with the intracellular domain of IFN-γ receptor and are activated by phosphorylation. The requisite recruitment site for signal transducer and activator of transcription (STAT) 1 is then formed, leading to STAT1 phosphorylation and homodimer formation. STAT1 homodimers translocate to the nucleus and ultimately bind to the DNA to modulate gene transcription (Figure 1). Besides the above mentioned canonical JAK-STAT pathway, IFN-γ signaling may involve noncanonical routes, such as endocytosis and ATP-dependent nuclear translocation of IFN-γ, IFN-γR1, JAK1, and JAK2 [11], which, as many other cytokines also use STAT1 as a transcription factor, might account for specific gene activation. In addition, several other kinases, including PI3K [12], CamKII [13], NF-κB [14], and ATM [15], either cooperate with or operate in parallel to JAK-STAT pathway for a full IFN-γ response. IFN-γ is produced by multiple cell types, including T cells (particularly Th1 subtype), B cells, monocytes/macrophages, and NK cells [16]. In RA synovium, CD8+ T cells are revealed to be the dominant source of IFN-γ, which is in contrast to the production of TNF-α by multiple T cell subsets, B cells, and monocytes and that of IL-6 by fibroblasts and B cells [17]. IFN-γ signaling can modulate a huge number of genes. There are more than 9,000 genes regulated by IFN-γ with two or more-fold changes [18]. Although many of genes regulated by IFN-γ are targets shared with type I IFN [19], specific functions of IFN-γ are suggested by the incomplete response to IFN-α therapy in some patients with IFN-γ receptor deficiency [20]. In physiological immunity, IFN-γ plays roles in production of reactive oxygen species, cytokine production, antigen presentation including MHC class II induction, metabolic pathways, cellular differentiation including macrophage activation (polarization towards M1 subtype), and cell growth and survival [16]. The fact that MHC class II variation (shared epitope) is the strongest genetic risk factor for RA raises a simple hypothesis that the MHC class II-inducing cytokine IFN-γ contributes to the development of RA. Polymorphisms in the IFN-γR2 gene are also associated with RA susceptibility [21].