Chris Monit

Approximate Bayesian computation (ABC) is a technique for modelling complicated systems using simulations instead of conventional statistical models.

CF has helped clients succeed with hospital capacity planning by building simulation models that give insight into patient pathways and forecast demand. We see an opportunity to use ABC for identifying drivers of long waiting lists.

ABC isn't widely known and in this blog post, I show how it can be applied to understand patient flow.

Background: Studying site-specific amino acid frequencies by eye can reveal biologically significant variability and lineage-specific adaptation. This so-called ‘sequence gazing’ often informs bioinformatics and experimental research. But it is important to also account for the underlying phylogeny, since similarities may be due to common descent rather than selection pressure, and because it is important to distinguish between founder effects and convergent evolution. We set out to combine… Show more

Background: Studying site-specific amino acid frequencies by eye can reveal biologically significant variability and lineage-specific adaptation. This so-called ‘sequence gazing’ often informs bioinformatics and experimental research. But it is important to also account for the underlying phylogeny, since similarities may be due to common descent rather than selection pressure, and because it is important to distinguish between founder effects and convergent evolution. We set out to combine phylogenetic and sequence data to produce evolutionarily insightful visualisations.

Results: We present ChromaClade, a convenient tool with a graphical user-interface that works in concert with popular tree viewers to produce colour-annotated phylogenies highlighting residues found in each taxon and at each site in a sequence alignment. Colouring branches according to residues found at descendent tips also quickly identifies lineage-specific residues and those internal branches where key substitutions have occurred. We demonstrate applications of ChromaClade to human immunodeficiency virus and influenza A virus datasets, illustrating cases of conservative, adaptive and convergent evolution.

Conclusions: We find this to be a powerful approach for visualising site-wise residue distributions and detecting evolutionary patterns, especially in large datasets. ChromaClade is available for Windows, macOS and Unix or Linux; program executables and source code are available at github.com/chrismonit/chroma_clade. Show less

Abstract: Animals defend themselves from viral infection using innate immunity proteins that disrupt various stages of the virus life cycle. In response, viruses produce proteins that bind these host factors and compromise their activity, resulting in evolutionary conflict as immunity and virus proteins adapt to prevent and restore binding, respectively. We report that evolutionary conflict involving the host innate immunity protein SAMHD1 has occurred throughout mammalian evolution. We observe… Show more

Abstract: Animals defend themselves from viral infection using innate immunity proteins that disrupt various stages of the virus life cycle. In response, viruses produce proteins that bind these host factors and compromise their activity, resulting in evolutionary conflict as immunity and virus proteins adapt to prevent and restore binding, respectively. We report that evolutionary conflict involving the host innate immunity protein SAMHD1 has occurred throughout mammalian evolution. We observe adaptation in a region of SAMHD1 that regulates its activity, and we demonstrate how mutations here influence its enzymatic properties, suggesting that evolutionary conflict has involved modulation of SAMHD1 regulation and function. This correlates with reduced restriction of HIV-1, indicating that positive selection has influenced both SAMHD1’s dNTPase and antiviral activities. Show less

Abstract: The rising prevalence of HIV drug resistance (HIVDR) could threaten gains made in combating the HIV epidemic and compromise the 90-90-90 target proposed by United Nations Programme on HIV/AIDS (UNAIDS) to have achieved virological suppression in 90% of all persons receiving antiretroviral therapy (ART) by the year 2020. HIVDR has implications for the persistence of HIV, the selection of current and future ART drug regimens, and strategies of vaccine and cure development. Focusing on… Show more

Abstract: The rising prevalence of HIV drug resistance (HIVDR) could threaten gains made in combating the HIV epidemic and compromise the 90-90-90 target proposed by United Nations Programme on HIV/AIDS (UNAIDS) to have achieved virological suppression in 90% of all persons receiving antiretroviral therapy (ART) by the year 2020. HIVDR has implications for the persistence of HIV, the selection of current and future ART drug regimens, and strategies of vaccine and cure development. Focusing on drug classes that are in clinical use, this Review critically summarizes what is known about the mechanisms the virus utilizes to escape drug control. Armed with this knowledge, strategies to limit the expansion of HIVDR are proposed. Show less

A well-publicised study showing the second ever case of an HIV positive patient entering remission, following a stem cell transplantation. I contributed mathematical modelling of virus evolution within the patient.

Summary
Existing ancestral sequence reconstruction techniques are ill-suited to investigating substitutions on a single branch of interest. We present SubRecon, an implementation of a hybrid technique integrating joint and marginal reconstruction for protein sequence data. SubRecon calculates the joint probability of states at adjacent internal nodes in a phylogeny, i.e. how the state has changed along a branch. This does not condition on states at other internal nodes and includes site rate… Show more

Summary
Existing ancestral sequence reconstruction techniques are ill-suited to investigating substitutions on a single branch of interest. We present SubRecon, an implementation of a hybrid technique integrating joint and marginal reconstruction for protein sequence data. SubRecon calculates the joint probability of states at adjacent internal nodes in a phylogeny, i.e. how the state has changed along a branch. This does not condition on states at other internal nodes and includes site rate variation. Simulation experiments show the technique to be accurate and powerful. SubRecon has a user-friendly command line interface and produces concise output that is intuitive yet suitable for subsequent parsing in an automated pipeline.

Availability and implementation
SubRecon is platform independent, requiring Java v1.8 or above. Source code, installation instructions and an example dataset are freely available under the Apache 2.0 license at https://github.com/chrismonit/SubRecon. Show less

In a recent AIDS Research and Human Retroviruses publication by C.N. Roy et al. [Intersubtype Genetic Variation of HIV-1 Tat Exon 1, 2015;33(6):1215–1225], the authors report the identification of 30 codon sites under positive selection in the first exon of the HIV-1 tat gene. Unfortunately, they have not considered the presence of overlapping coding sequences in HIV-1, invalidating most of their positive selection analysis.