A closer look at parameter identifiability, model selection and handling of censored data with Bayesian Inference in mathematical models of tumour growth

Mathematical models (MMs) are a powerful tool to help us understand and predict the dynamics of tumour growth under various conditions. In this work, we use 5 MMs with an increasing number of parameters to explore how certain (often overlooked) decisions in estimating parameters from data of experimental tumour growth affect the outcome of the analysis. In particular, we propose a framework for including tumour volume measurements that fall outside the upper and lower limits of detection, which are normally discarded. We demonstrate how excluding censored data results in an overestimation of the initial tumour volume and the MM-predicted tumour volumes prior to the first measurements, and an underestimation of the carrying capacity and the MM-predicted tumour volumes beyond the latest measurable time points. We show in which way the choice of prior for the MM parameters can impact the posterior distributions, and illustrate that reporting the highest-likelihood parameters and their 95% credible interval can lead to confusing or misleading interpretations. We hope this work will encourage others to carefully consider choices made in parameter estimation and to adopt the approaches we put forward herein.Comment: 15 pages, 7 figure

The Human Phenotype Ontology project:linking molecular biology and disease through phenotype data

The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online

Looking at Cerebellar Malformations through Text-Mined Interactomes of Mice and Humans

WE HAVE GENERATED AND MADE PUBLICLY AVAILABLE TWO VERY LARGE NETWORKS OF MOLECULAR INTERACTIONS: 49,493 mouse-specific and 52,518 human-specific interactions. These networks were generated through automated analysis of 368,331 full-text research articles and 8,039,972 article abstracts from the PubMed database, using the GeneWays system. Our networks cover a wide spectrum of molecular interactions, such as bind, phosphorylate, glycosylate, and activate; 207 of these interaction types occur more than 1,000 times in our unfiltered, multi-species data set. Because mouse and human genes are linked through an orthological relationship, human and mouse networks are amenable to straightforward, joint computational analysis. Using our newly generated networks and known associations between mouse genes and cerebellar malformation phenotypes, we predicted a number of new associations between genes and five cerebellar phenotypes (small cerebellum, absent cerebellum, cerebellar degeneration, abnormal foliation, and abnormal vermis). Using a battery of statistical tests, we showed that genes that are associated with cerebellar phenotypes tend to form compact network clusters. Further, we observed that cerebellar malformation phenotypes tend to be associated with highly connected genes. This tendency was stronger for developmental phenotypes and weaker for cerebellar degeneration

SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant

Mutual Information Based Methods to Localize Image Registration

Modern medicine has become reliant on medical imaging. Multiple modalities, e. g. magnetic resonance imaging (MRI), computed tomography (CT), etc. , are used to provide as much information about the patient as possible. The problem of geometrically aligning the resulting images is called image registration. Mutual information, an information theoretic similarity measure, allows for automated intermodal image registration algorithms. In applications such as cancer therapy, diagnosticians are more concerned with the alignment of images over a region of interest such as a cancerous lesion, than over an entire image set. Attempts to register only the regions of interest, defined manually by diagnosticians, fail due to inaccurate mutual information estimation over the region of overlap of these small regions. This thesis examines the region of union as an alternative to the region of overlap. We demonstrate that the region of union improves the accuracy and reliability of mutual information estimation over small regions. We also present two new mutual information based similarity measures which allow for localized image registration by combining local and global image information. The new similarity measures are based on convex combinations of the information contained in the regions of interest and the information contained in the global images. Preliminary results indicate that the proposed similarity measures are capable of localizing image registration. Experiments using medical images from computer tomography and positron emission tomography demonstrate the initial success of these measures. Finally, in other applications, auto-detection of regions of interest may prove useful and would allow for fully automated localized image registration. We examine methods to automatically detect potential regions of interest based on local activity level and present some encouraging results

A MATHEMATICAL ANALYSIS OF PHYSIOLOGICAL AND MOLECULAR MECHANISMS THAT MODULATE PRESSURE GRADIENTS AND FACILITATE VENTRICULAR EXPANSION IN HYDROCEPHALUS

Abstract. Perhaps the greatest paradox in the hydrocephalus field is the failure of researchers to consistently measure transmantle pressure gradients (ventricle to subarachnoid space) in either human or animal models of the communicating form of the disorder. Without such a gradient, conceptualization of how ventricular distention occurs is difficult. Based on evidence from both a mathematical model [35] and experiments in skin [51], we observed that the intraventricular injection of anti-β1 integrin antibodies in rat brains results in a reduction of periventricular pressures to values below those monitored in the ventricles. In addition, many of these animals developed hydrocephalus [30]. We conclude that the dissociation of β1 integrins from the surrounding matrix fibers generates pressure gradients favouring ventricular expansion suggesting a novel mechanism for hydrocephalus development. Several issues, however, need further clarification. If hydrostatic pressure declines in the periventricular tissues then fluid absorption must occur. Aquaporin-4 (AQP4) is a likely candidate for this absorption as it is the predominant water channel in the brain. Indeed, when capillary function is negated, periventricular interstitial fluid pressures increase after anti-β1 integrin antibody administration. This suggests that capillary absorption of parenchymal water may play a pivotal role in the generation of pressure gradients in our hydrocephalus model. Focusing on these issues, we present two poroelastic models to investigate the role of intramantle pressure gradients in ventriculomegaly and to determine if integrin-matrix disassociation represents a complete causative mechanism for hydrocephalus development. Key words. Hydrocephalus, β1 Integrins, Aquaporin-4, Brain Biomechanics, Poroelasticity. 1

Computing and Information A MATHEMATICAL INVESTIGATION OF THE ROLE OF INTRACRANIAL PRESSURE PULSATIONS AND SMALL GRADIENTS IN THE PATHOGENESIS OF HYDROCEPHALUS

Abstract. Cerebrospinal fluid (CSF) pulsations have been proposed as a possible causative mechanism for the ventricular enlargement that characterizes the neurological condition known as hydrocephalus. This paper summarizes recent work by the authors to anaylze the effect of CSF pulsations on brain tissue to determine if they are mechanically capable of enlarging the cerebral ventricles. First a poroelastic model is presented to analyze the interactions that occur between the fluid and porous solid constituents of brain tissue due to CSF pulsations. A viscoelastic model is then presented to analyze the effects of the fluid pulsations on the solid brain tissue. The combined results indicate that CSF pulsations in a healthy brain are incapable of causing tissue damage and thus the ventricular enlargement observed in hydrocephalus. Therefore they cannot be the primary cause of this condition. Finally, a hyper-viscoelastic model is presented and used to demonstrate that small long-term transmantle pressure gradients may be a possible cause of communicating hydrocephalus in infants