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"Wilson, Daniel"
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The harmonic mean p-value for combining dependent tests
Analysis of “big data” frequently involves statistical comparison of millions of competing hypotheses to discover hidden processes underlying observed patterns of data, for example, in the search for genetic determinants of disease in genome-wide association studies (GWAS). Controlling the familywise error rate (FWER) is considered the strongest protection against false positives but makes it difficult to reach the multiple testing-corrected significance threshold. Here, I introduce the harmonic mean p-value (HMP), which controls the FWER while greatly improving statistical power by combining dependent tests using generalized central limit theorem. I show that the HMP effortlessly combines information to detect statistically significant signals among groups of individually nonsignificant hypotheses in examples of a human GWAS for neuroticism and a joint human–pathogen GWAS for hepatitis C viral load. The HMP simultaneously tests all ways to group hypotheses, allowing the smallest groups of hypotheses that retain significance to be sought. The power of the HMP to detect significant hypothesis groups is greater than the power of the Benjamini–Hochberg procedure to detect significant hypotheses, although the latter only controls the weaker false discovery rate (FDR). The HMP has broad implications for the analysis of large datasets, because it enhances the potential for scientific discovery.
Journal Article
Guardian angels & other monsters : stories
A collection of stories that explores complex emotional and intellectual landscapes at the intersection of artificial intelligence and human life.
Book
ClonalFrameML: Efficient Inference of Recombination in Whole Bacterial Genomes
Recombination is an important evolutionary force in bacteria, but it remains challenging to reconstruct the imports that occurred in the ancestry of a genomic sample. Here we present ClonalFrameML, which uses maximum likelihood inference to simultaneously detect recombination in bacterial genomes and account for it in phylogenetic reconstruction. ClonalFrameML can analyse hundreds of genomes in a matter of hours, and we demonstrate its usefulness on simulated and real datasets. We find evidence for recombination hotspots associated with mobile elements in Clostridium difficile ST6 and a previously undescribed 310kb chromosomal replacement in Staphylococcus aureus ST582. ClonalFrameML is freely available at http://clonalframeml.googlecode.com/.
Journal Article
Amped : a novel
In a near-future world where technologically enhanced humans are governed by a strict set of conduct laws, twenty-nine-year-old Owen Gray joins the ranks of a persecuted underclass that is planning to change, or destroy, the world.
Book
Ribosome-targeting antibiotics and mechanisms of bacterial resistance
Key Points
The bacterial ribosome is one of the main targets of antibiotics, with most clinically used antibiotics targeting either the decoding site on the small ribosomal subunit (30S subunit) or the peptidyl-transferase centre on the large subunit (50S subunit).
The majority of antibiotics that target the 30S subunit inhibit protein synthesis by preventing either the binding of tRNAs to the ribosome or the movement of tRNAs through the ribosome during translocation.
Most antibiotics that target the 50S subunit inhibit protein synthesis by either perturbing the binding of aminoacylated-tRNAs at the A- or P-sites or preventing the channelling of the nascent polypeptide chain through the ribosomal tunnel.
Bacterial antibiotic resistance mechanisms include efflux, reduced influx, modification and degradation of the drug, as well as mutation, modification or overexpression of the target.
The majority of ribosome-targeting antibiotics in clinical trials are semi-synthetic derivatives of naturally produced compounds, but further work will be required to develop antibiotics that target novel sites on the ribosome.
The ribosome is one of the primary antibiotic targets in the bacterial cell. Here, Daniel Wilson discusses how high-resolution crystal structures of antibiotic–ribosome complexes have provided molecular insight into the mechanisms of antibiotic action and bacterial resistance, in addition to the approaches being pursued for the development of improved and novel ribosome-targeting antibiotics.
The ribosome is one of the main antibiotic targets in the bacterial cell. Crystal structures of naturally produced antibiotics and their semi-synthetic derivatives bound to ribosomal particles have provided unparalleled insight into their mechanisms of action, and they are also facilitating the design of more effective antibiotics for targeting multidrug-resistant bacteria. In this Review, I discuss the recent structural insights into the mechanism of action of ribosome-targeting antibiotics and the molecular mechanisms of bacterial resistance, in addition to the approaches that are being pursued for the production of improved drugs that inhibit bacterial protein synthesis.
Journal Article
The clockwork dynasty : a novel
\"In the rugged landscape of eastern Oregon, a young scientist named June uncovers an exquisite artifact--a three-hundred-year-old mechanical doll whose existence seems to validate her obsession with a harrowing story she was told by her grandfather many years earlier. The mechanical doll, June believes, is proof of a living race of automatons that walk undetected among us to this day. Ingeniously hidden inside the ancient doll is a lost message, addressed to the court of Peter the Great, czar of Russia. Russia, 1725: Peter and Elena, two human-like mechanical beings, are brought to life under the watchful guise of Peter the Great. Their struggle to serve in the court of the czar while blending in, and to survive amid those who fear and wish to annihilate them, will take Peter and Elena across Russia, Europe, and, ultimately, across the centuries to modern day.\"-- Provided by publisher.
Book
The Effect of State Taxes on the Geographical Location of Top Earners: Evidence from Star Scientists
We quantify how sensitive is migration by star scientists to changes in personal and business tax differentials across states. We uncover large, stable, and precisely estimated effects of personal and corporate taxes on star scientists' migration patterns. The long-run elasticity of mobility relative to taxes is 1.8 for personal income taxes, 1.9 for state corporate income tax, and — 1.7 for the investment tax credit. While there are many other factors that drive when innovative individuals and innovative companies decide to locate, there are enough firms and workers on the margin that state taxes matter.
Journal Article
Robogenesis : a novel
\"It's been three years since the global uprising of the world's robots, three long years in which ordinary people waged a guerrilla war that saved humankind from the brink of annihilation. But a horrific new enemy has emerged, and the resistance is called to fight once again. And in the world where humanity and technology are pushed to the breaking point, their one hope may reside with their former enemy - Archos R-14\"--Back cover.
Book
Operative management of fragility fractures of the pelvis – a systematic review
Background
The incidence of osteoporotic pelvic fractures in elderly patient is rising. This brings an increasing burden on health and social care systems as these injuries often lead to prolonged hospital admissions, loss of independence, morbidity and mortality. Some centres now advocate stabilisation of these injuries to reduce pain, facilitate early mobilisation, decrease hospital stay and restore independence. A systematic review of the literature was planned to establish the evidence for this intervention.
Methods
A systematic review was performed according to PRISMA guidelines. A clinical librarian performed a search of the following databases: NHS Evidence, TRIP, the Cochrane Database of Systematic Reviews, MEDLINE and EMBASE. Seventeen eligible studies were identified with 766 patients.
Results
The quality of evidence was poor with no good quality randomised trials. The majority of injuries were minimally displaced. Posterior ring injuries were most often stabilised with percutaneous screws which were sometimes augmented with void filler. A number of techniques were described for stabilisation of the anterior ring although fixation of the anterior ring was frequently not performed.
There was consistent evidence from the included studies that operative intervention significantly improved pain. Complications were minimal but there were increased failure rates when a single unaugmented sacroiliac joint screw was used. The limited availability of non-operative comparators made it difficult to draw firm conclusions about the efficacy of surgical over non-surgical management in these patients.
Conclusions
Operative management of fragility fractures of the pelvis should be considered for patients failing a brief period of non-operative management, however prospective randomised trials need to be performed to provide improved evidence for this intervention. Surgeons should consider which fixation techniques for fragility fractures of the pelvis are robust enough to allow immediate weightbearing, whilst minimising operative morbidity and post-operative complications.
PROSPERO Systematic Review ID: CRD42020171237.
Journal Article