Bayesian tests of symmetry for the generalized Von Mises distribution

Bayesian tests on the symmetry of the generalized von Mises model for planar directions (Gatto and Jammalamadaka in Stat Methodol 4(3):341–353, 2007) are introduced. The generalized von Mises distribution is a flexible model that can be axially symmetric or asymmetric, unimodal or bimodal. A characterization of axial symmetry is provided and taken as null hypothesis for one of the proposed Bayesian tests. The Bayesian tests are obtained by the technique of probability perturbation. The prior probability measure is perturbed so to give a positive prior probability to the null hypothesis, which would be null otherwise. This allows for the derivation of simple computational formulae for the Bayes factors. Numerical results reveal that, whenever the simulation scheme of the samples supports the null hypothesis, the null posterior probabilities appear systematically larger than their prior counterpart.

Adaptive treatment allocation and selection in multi-arm clinical trials: a Bayesian perspective

Background: Adaptive designs offer added flexibility in the execution of clinical trials, including the possibilities of allocating more patients to the treatments that turned out more successful, and early stopping due to either declared success or futility. Commonly applied adaptive designs, such as group sequential methods, are based on the frequentist paradigm and on ideas from statistical significance testing. Interim checks during the trial will have the effect of inflating the Type 1 error rate, or, if this rate is controlled and kept fixed, lowering the power. Results: The purpose of the paper is to demonstrate the usefulness of the Bayesian approach in the design and in the actual running of randomized clinical trials during Phase II and III. This approach is based on comparing the performance of the different treatment arm in terms of the respective joint posterior probabilities evaluated sequentially from the accruing outcome data, and then taking a control action if such posterior probabilities fall below a pre-specified critical threshold value. Two types of actions are considered: treatment allocation, putting on hold at least temporarily further accrual of patients to a treatment arm (Rule 1), and treatment selection, removing an arm from the trial permanently (Rule 2). The main development in the paper is in terms of binary outcomes, but extensions for handling time-to-event data, including data from vaccine trials, are also discussed. The performance of the proposed methodology is tested in extensive simulation experiments, with numerical results and graphical illustrations documented in a Supplement to the main text. As a companion to this paper, an implementation of the methods is provided in the form of a freely available R package. Conclusion: The proposed methods for trial design provide an attractive alternative to their frequentist counterparts.

Preoperative Radiomics Analysis of 1p/19q Status in WHO Grade II Gliomas

PurposeThe present study aimed to preoperatively predict the status of 1p/19q based on radiomics analysis in patients with World Health Organization (WHO) grade II gliomas.MethodsThis retrospective study enrolled 157 patients with WHO grade II gliomas (76 patients with astrocytomas with mutant IDH, 16 patients with astrocytomas with wild-type IDH, and 65 patients with oligodendrogliomas with mutant IDH and 1p/19q codeletion). Radiomic features were extracted from magnetic resonance images, including T1-weighted, T2-weighted, and contrast T1-weighted images. Elastic net and support vector machines with radial basis function kernel were applied in nested 10-fold cross-validation loops to predict the 1p/19q status. Receiver operating characteristic analysis and precision-recall analysis were used to evaluate the model performance. Student’s t-tests were then used to compare the posterior probabilities of 1p/19q co-deletion prediction in the group with different 1p/19q status.ResultsSix valuable radiomic features, along with age, were selected with the nested 10-fold cross-validation loops. Five features showed significant difference in patients with different 1p/19q status. The area under curve and accuracy of the predictive model were 0.8079 (95% confidence interval, 0.733–0.8755) and 0.758 (0.6879–0.8217), respectively, and the F1-score of the precision-recall curve achieved 0.6667 (0.5201–0.7705). The posterior probabilities in the 1p/19q co-deletion group were significantly different from the non-deletion group.ConclusionCombined radiomics analysis and machine learning showed potential clinical utility in the preoperative prediction of 1p/19q status, which can aid in making customized neurosurgery plans and glioma management strategies before postoperative pathology.

Effectiveness of Tocilizumab, Sarilumab, and Anakinra for critically ill patients with COVID-19 The REMAP-CAP COVID-19 Immune Modulation Therapy Domain Randomized Clinical Trial

BACKGROUND: The interleukin-6 receptor antagonist tocilizumab improves outcomes in critically ill patients with coronavirus disease 2019 (COVID-19). However, the effectiveness of other immune modulating agents is unclear. METHODS: We evaluated four immunomodulatory agents in an ongoing international, multifactorial, adaptive platform trial. Adult participants with COVID-19 were randomized to receive tocilizumab, sarilumab, anakinra, or standard care (control). In addition, a small group (n=21) of participants were randomized to interferon-beta1a. The primary outcome was an ordinal scale combining in-hospital mortality (assigned -1) and days free of organ support to day 21. The trial used a Bayesian statistical model with pre-defined triggers for superiority, equivalence or futility. RESULTS: Statistical triggers for equivalence between tocilizumab and sarilumab; and for inferiority of anakinra to the other active interventions were met at a planned adaptive analysis. Of the 2274 critically ill participants enrolled, 972 were assigned to tocilizumab, 485 to sarilumab, 378 to anakinra and 418 to control. Median organ support-free days were 7 (interquartile range [IQR] -1, 16), 9 (IQR -1, 17), 0 (IQR -1, 15) and 0 (IQR -1, 15) for tocilizumab, sarilumab, anakinra and control, respectively. Median adjusted odds ratios were 1.46 (95%CrI 1.13, 1.87), 1.50 (95%CrI 1.13, 2.00), and 0.99 (95%CrI 0.74, 1.35) for tocilizumab, sarilumab and anakinra, yielding 99.8%, 99.8% and 46.6% posterior probabilities of superiority, respectively, compared to control. Median adjusted odds ratios for hospital survival were 1.42 (95%CrI 1.05,1.93), 1.51 (95%CrI 1.06, 2.20) and 0.97 (95%CrI 0.66, 1.40) for tocilizumab, sarilumab and anakinra respectively, compared to control, yielding 98.8%, 98.8% and 43.6% posterior probabilities of superiority, respectively, compared to control. All treatments appeared safe. CONCLUSIONS: In patients with severe COVID-19 receiving organ support, tocilizumab and sarilumab are similarly effective at improving survival and reducing duration of organ support. Anakinra is not effective in this population.

Tocilizumab in COVID-19 – A Bayesian reanalysis of RECOVERY

Background: Randomised Evaluation of COVID-19 Therapy (RECOVERY) demonstrated that tocilizumab reduces mortality in hospitalized COVID-19 patients. However, substantial uncertainty remains whether tocilizumab's effect is similar across clinically relevant subgroups. Whether this uncertainty can be resolved with Bayesian methods is unknown. Design, Setting, Participants, and Interventions: RECOVERY was a controlled, open-label, platform UK trial that randomized (1:1) 4116 adults with oxygen saturation <92% on room air or receiving oxygen therapy with C-reactive protein ≥75 mg/L to either usual care or tocilizumab plus usual care. Main outcome measures: Mortality and hospital discharge within 28 days. Methods: Using Bayesian methods, we combined RECOVERY with evidence-based priors incorporating previous COVID-19 tocilizumab RCTs. The probability of tocilizumab's benefit for respiratory support and corticosteroid subgroups and sensitivity analyses were performed with different prior distributions and baseline risks. Results: For all-cause mortality, the posterior probabilities of decreased deaths with tocilizumab were >99% and 19% in patients using and not using corticosteroids, respectively. In patients on simple oxygen only, non-invasive ventilation and invasive mechanical ventilation, the probabilities of decreased mortality were 96%, >99% and 77%, respectively. The probabilities for a clinically significant mortality reduction, as assessed by an absolute risk difference > 3% (number needed to treat ≤ 33), were 77%, 96%, 56%, respectively. Sensitivity analyses highlighted the uncertainty and lack of conclusive evidence for tocilizumab's effect in patients on invasive mechanical ventilation and those without concurrent corticosteroids. Posterior probabilities of benefit for hospital discharge outcome were high and consistent across most subgroups. Conclusions: In this Bayesian reanalysis, COVID-19 hospitalized patients exposed to corticosteroids or on non-invasive ventilation have a high probability of a clinically meaningful mortality benefit from tocilizumab. Tocilizumab also likely improves discharge from hospital in most subgroups. Future research should further address if patients on invasive mechanical ventilation can also benefit from tocilizumab.

Highly rearranged mitochondrial genome in Falcolipeurus lice (Phthiraptera: Philopteridae) from endangered eagles

Background Fragmented mitochondrial (mt) genomes and extensive mt gene rearrangements have been frequently reported from parasitic lice (Insecta: Phthiraptera). However, relatively little is known about the mt genomes from the family Philopteridae, the most species-rich family within the suborder Ischnocera. Methods Herein, we use next-generation sequencing to decode the mt genome of Falcolipeurus suturalis and compare it with the mt genome of F. quadripustulatus. Phylogenetic relationships within the family Philopteridae were inferred from the concatenated 13 protein-coding genes of the two Falcolipeurus lice and members of the family Philopteridae using Bayesian inference (BI) and maximum likelihood (ML) methods. Results The complete mt genome of F. suturalis is a circular, double-stranded DNA molecule 16,659 bp in size that contains 13 protein-coding genes, 22 transfer RNA genes, two ribosomal RNA genes, and three non-coding regions. The gene order of the F. suturalis mt genome is rearranged relative to that of F. quadripustulatus, and is radically different from both other louse species and the putative ancestral insect. Phylogenetic analyses revealed clear genetic distinctiveness between F. suturalis and F. quadripustulatus (Bayesian posterior probabilities = 1.0 and bootstrapping frequencies = 100), and that the genus Falcolipeurus is sister to the genus Ibidoecus (Bayesian posterior probabilities = 1.0 and bootstrapping frequencies = 100). Conclusions These datasets help to better understand gene rearrangements in lice and the phylogenetic position of Falcolipeurus and provide useful genetic markers for systematic studies of bird lice. Graphic abstract

Phylogenetics of native conifer species in Vietnam based on two chloroplast gene regions rbcL and matK

We used two chloroplast gene regions (matK and rbcL) as a tool for the identification of 33 local conifer species. All 136 sequences, 101 newly generated (14 species for gene matK; 16 species for gene rbcL) and 35 retrieved from the GenBank, were used in the analysis. The highest genetic distance (matK region) was recorded between the species in Cupressaceae with an average of 5% (0.1–8.5), Podocarpaceae with an average of 6% (0–8.5), Taxaceae with an average of 5% (0.2–0.5) and Pinaceae with an average of 20.4% (0.8–54.1). The rbcL region showed a low genetic distance between the species in Cupressaceae 2% (0–3.3), Podocarpaceae 3% (0.6–3.4), Taxaceae 1% (0–2.1) and Pinaceae 1.2% (0–5.82). The phylogenetic analyses using the Maximum likelihood (ML) and Bayesian inference (BI) bootstrap values obtained at the branching nodes of each species ranged from 62 to 100% (Maximum likelihood bootstrap – MLBS and Bayesian posterior probabilities – BPP) for the matK gene; from 66 to 100% (MLBS) and 60 to 100% (BPP) for the rbcL region. The rbcL region was not identified between the species of Taxaceae and Cephalotaxaceae. The matK gene region was very clear in the different species among the families (Cupressaceae, Podocarpaceae, and Cephalotaxaceae) and unsuitable for identifying closely related species in Amentotaxus (Taxaceae) and Pinus (Pinaceae). The gene (matK) is a useful tool as a barcode in the identification of conifer species of Cupressaceae, Podocarpaceae, and Cephalotaxaceae in Vietnam.

BATL: Bayesian annotations for targeted lipidomics

Motivation: Bioinformatic tools capable of annotating, rapidly and reproducibly, large targeted lipidomic datasets are limited. Specifically, few programs enable high-throughput peak assessment of liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) data acquired in either selected or multiple reaction monitoring (SRM and MRM) modes. Results: We present here Bayesian Annotations for Targeted Lipidomics (BATL), a Gaussian naive Bayes classifier for targeted lipidomics, that annotates peak identities according to eight features related to retention time, intensity, and peak shape. Lipid identification is achieved by modelling distributions of these eight input features across biological conditions and maximizing the joint posterior probabilities of all peak identities at a given transition. When applied to sphingolipid and glycerophosphocholine SRM datasets, we demonstrate over 95% of all peaks are rapidly and correctly identified. Availability: The BATL software is available on GitHub at https://github.com/lipidomic-uottawa/batl Contact: [email protected] and [email protected]