Mathematical Model of HIV superinfection dynamics and R5 to X4 switch

During the HIV infection several quasispecies of the virus arise, which are able to use different coreceptors, in particular the CCR5 and CXCR4 coreceptors (R5 and X4 phenotypes, respectively). The switch in coreceptor usage has been correlated with a faster progression of the disease to the AIDS phase. As several pharmaceutical companies are starting large phase III trials for R5 and X4 drugs, models are needed to predict the co-evolutionary and competitive dynamics of virus strains. We present a model of HIV early infection which describes the dynamics of R5 quasispecies and a model of HIV late infection which describes the R5 to X4 switch. We report the following findings: after superinfection or coinfection, quasispecies dynamics has time scales of several months and becomes even slower at low number of CD4+ T cells. The curve of CD4+ T cells decreases, during AIDS late stage, and can be described taking into account the X4 related Tumor Necrosis Factor dynamics. Phylogenetic inference of chemokine receptors suggests that viral mutational pathway may generate R5 variants able to interact with chemokine receptors different from CXCR4. This may explain the massive signaling disruptions in the immune system observed during AIDS late stages and may have relevance for vaccination and therapy.Comment: 21 pages, 14 figure

Investigating meta-approaches for reconstructing gene networks in a mammalian cellular context.

The output of state-of-the-art reverse-engineering methods for biological networks is often based on the fitting of a mathematical model to the data. Typically, different datasets do not give single consistent network predictions but rather an ensemble of inconsistent networks inferred under the same reverse-engineering method that are only consistent with the specific experimentally measured data. Here, we focus on an alternative approach for combining the information contained within such an ensemble of inconsistent gene networks called meta-analysis, to make more accurate predictions and to estimate the reliability of these predictions. We review two existing meta-analysis approaches; the Fisher transformation combined coefficient test (FTCCT) and Fisher's inverse combined probability test (FICPT); and compare their performance with five well-known methods, ARACNe, Context Likelihood or Relatedness network (CLR), Maximum Relevance Minimum Redundancy (MRNET), Relevance Network (RN) and Bayesian Network (BN). We conducted in-depth numerical ensemble simulations and demonstrated for biological expression data that the meta-analysis approaches consistently outperformed the best gene regulatory network inference (GRNI) methods in the literature. Furthermore, the meta-analysis approaches have a low computational complexity. We conclude that the meta-analysis approaches are a powerful tool for integrating different datasets to give more accurate and reliable predictions for biological networks

Prior and Likelihood Choices for Bayesian Matrix Factorisation on Small Datasets

In this paper, we study the effects of different prior and likelihood choices for Bayesian matrix factorisation, focusing on small datasets. These choices can greatly influence the predictive performance of the methods. We identify four groups of approaches: Gaussian-likelihood with real-valued priors, nonnegative priors, semi-nonnegative models, and finally Poisson-likelihood approaches. For each group we review several models from the literature, considering sixteen in total, and discuss the relations between different priors and matrix norms. We extensively compare these methods on eight real-world datasets across three application areas, giving both inter- and intra-group comparisons. We measure convergence runtime speed, cross-validation performance, sparse and noisy prediction performance, and model selection robustness. We offer several insights into the trade-offs between prior and likelihood choices for Bayesian matrix factorisation on small datasets - such as that Poisson models give poor predictions, and that nonnegative models are more constrained than real-valued ones

PECLIDES Neuro: A Personalisable Clinical Decision Support System for Neurological Diseases.

Neurodegenerative diseases such as Alzheimer's and Parkinson's impact millions of people worldwide. Early diagnosis has proven to greatly increase the chances of slowing down the diseases' progression. Correct diagnosis often relies on the analysis of large amounts of patient data, and thus lends itself well to support from machine learning algorithms, which are able to learn from past diagnosis and see clearly through the complex interactions of a patient's symptoms and data. Unfortunately, many contemporary machine learning techniques fail to reveal details about how they reach their conclusions, a property considered fundamental when providing a diagnosis. Here we introduce our Personalisable Clinical Decision Support System (PECLIDES), an algorithmic process formulated to address this specific fault in diagnosis detection. PECLIDES provides a clear insight into the decision-making process leading to a diagnosis, making it a gray box model. Our algorithm enriches the fundamental work of Masheyekhi and Gras in data integration, personal medicine, usability, visualization, and interactivity. Our decision support system is an operation of translational medicine. It is based on random forests, is personalisable and allows a clear insight into the decision-making process. A well-structured rule set is created and every rule of the decision-making process can be observed by the user (physician). Furthermore, the user has an impact on the creation of the final rule set and the algorithm allows the comparison of different diseases as well as regional differences in the same disease. The algorithm is applicable to various decision problems. In this paper we will evaluate it on diagnosing neurological diseases and therefore refer to the algorithm as PECLIDES Neuro