A programme for risk assessment and minimisation of progressive multifocal leukoencephalopathy developed for vedolizumab clinical trials

Introduction Over the past decade, the potential for drug-associated progressive multifocal leukoencephalopathy (PML) has become an increasingly important consideration in certain drug development programmes, particularly those of immunomodulatory biologics. Whether the risk of PML with an investigational agent is proven (e.g. extrapolated from relevant experience, such as a class effect) or merely theoretical, the serious consequences of acquiring PML require careful risk minimisation and assessment. No single standard for such risk minimisation exists. Vedolizumab is a recently developed monoclonal antibody to α4β7 integrin. Its clinical development necessitated a dedicated PML risk minimisation assessment as part of a global preapproval regulatory requirement. Objective The aim of this study was to describe the multiple risk minimisation elements that were incorporated in vedolizumab clinical trials in inflammatory bowel disease patients as part of the risk assessment and minimisation of PML programme for vedolizumab. Methods A case evaluation algorithm was developed for sequential screening and diagnostic evaluation of subjects who met criteria that indicated a clinical suspicion of PML. An Independent Adjudication Committee provided an independent, unbiased opinion regarding the likelihood of PML. Results Although no cases were detected, all suspected PML events were thoroughly reviewed and successfully adjudicated, making it unlikely that cases were missed. Conclusion We suggest that this programme could serve as a model for pragmatic screening for PML during the clinical development of new drugs

Practical probabilistic programming with monads

The machine learning community has recently shown a lot of interest in practical probabilistic programming systems that target the problem of Bayesian inference. Such systems come in different forms, but they all express probabilistic models as computational processes using syntax resembling programming languages. In the functional programming community monads are known to offer a convenient and elegant abstraction for programming with probability distributions, but their use is often limited to very simple inference problems. We show that it is possible to use the monad abstraction to construct probabilistic models for machine learning, while still offering good performance of inference in challenging models. We use a GADT as an underlying representation of a probability distribution and apply Sequential Monte Carlo-based methods to achieve efficient inference. We define a formal semantics via measure theory. We demonstrate a clean and elegant implementation that achieves performance comparable with Anglican, a state-of-the-art probabilistic programming system.The first author is supported by EPSRC and the Cambridge Trust.This is the author accepted manuscript. The final version is available from ACM via http://dx.doi.org/10.1145/2804302.280431

Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis

;irikizumab, a p19-directed antibody against interleukin-23, showed efficacy in the treatment of ulcerative colitis in a phase 2 trial. Methods: We conducted two phase 3, randomized, double-blind, placebo-controlled trials of mirikizumab in adults with moderately to severely active ulcerative colitis. In the induction trial, patients were randomly assigned in a 3:1 ratio to receive mirikizumab (300 mg) or placebo, administered intravenously, every 4 weeks for 12 weeks. In the maintenance trial, patients with a response to mirikizumab induction therapy were randomly assigned in a 2:1 ratio to receive mirikizumab (200 mg) or placebo, administered subcutaneously, every 4 weeks for 40 weeks. The primary end points were clinical remission at week 12 in the induction trial and at week 40 (at 52 weeks overall) in the maintenance trial. Major secondary end points included clinical response, endoscopic remission, and improvement in bowel-movement urgency. Patients who did not have a response in the induction trial were allowed to receive open-label mirikizumab during the first 12 weeks of the maintenance trial as extended induction. Safety was also assessed. Results: A total of 1281 patients underwent randomization in the induction trial, and 544 patients with a response to mirikizumab underwent randomization again in the maintenance trial. Significantly higher percentages of patients in the mirikizumab group than in the placebo group had clinical remission at week 12 of the induction trial (24.2% vs. 13.3%, P<0.001) and at week 40 of the maintenance trial (49.9% vs. 25.1%, P<0.001). The criteria for all the major secondary end points were met in both trials. Adverse events of nasopharyngitis and arthralgia were reported more frequently with mirikizumab than with placebo. Among the 1217 patients treated with mirikizumab during the controlled and uncontrolled periods (including the open-label extension and maintenance periods) in the two trials, 15 had an opportunistic infection (including 6 with herpes zoster infection) and 8 had cancer (including 3 with colorectal cancer). Among the patients who received placebo in the induction trial, 1 had herpes zoster infection and none had cancer. Conclusions: Mirikizumab was more effective than placebo in inducing and maintaining clinical remission in patients with moderately to severely active ulcerative colitis. Opportunistic infection or cancer occurred in a small number of patients treated with mirikizuma

Performing television history

An expanded conception of performance study can disturb current theoretical and historical assumptions about television’s medial identity. The article considers how to write histories of the dominant forms and assumptions about performance in British and American television drama, and analyses how acting is situated in relation to the multiple meaning-making components of television. A longitudinal, wide-ranging analysis is briefly sketched to show that the concept of performance, from acting to the display of television’s mediating capability, can extend to the analysis of how the television medium ‘performed’ its own identity to shape its distinctiveness in specific historical circumstances

Probabilistic machine learning and artificial intelligence.

How can a machine learn from experience? Probabilistic modelling provides a framework for understanding what learning is, and has therefore emerged as one of the principal theoretical and practical approaches for designing machines that learn from data acquired through experience. The probabilistic framework, which describes how to represent and manipulate uncertainty about models and predictions, has a central role in scientific data analysis, machine learning, robotics, cognitive science and artificial intelligence. This Review provides an introduction to this framework, and discusses some of the state-of-the-art advances in the field, namely, probabilistic programming, Bayesian optimization, data compression and automatic model discovery.The author acknowledges an EPSRC grant EP/I036575/1, the DARPA PPAML programme, a Google Focused Research Award for the Automatic Statistician and support from Microsoft Research.This is the author accepted manuscript. The final version is available from NPG at http://www.nature.com/nature/journal/v521/n7553/full/nature14541.html#abstract

Probabilistic Programming

Probabilistic programs are usual functional or imperative programs with two added constructs: (1) the ability to draw values at random from distributions, and (2) the ability to condition values of variables in a program via observations. Models from diverse application areas such as computer vision, coding theory, cryptographic protocols, biology and reliability analysis can be written as probabilistic programs. Probabilistic inference is the problem of computing an explicit representation of the probability distribution implicitly specified by a probabilistic program. Depending on the application, the desired output from inference may vary-we may want to estimate the expected value of some function f with respect to the distribution, or the mode of the distribution, or simply a set of samples drawn from the distribution. In this paper, we describe connections this research area called \Probabilistic Programming&quot; has with programming languages and software engineering, and this includes language design, and the static and dynamic analysis of programs. We survey current state of the art and speculate on promising directions for future research

International consensus definition of low anterior resection syndrome

BACKGROUND: Low anterior resection syndrome is pragmatically defined as disordered bowel function after rectal resection leading to a detriment in quality of life. This broad characterization does not allow for precise estimates of prevalence. The low anterior resection syndrome score was designed as a simple tool for clinical evaluation of low anterior resection syndrome. Although the low anterior resection syndrome score has good clinical utility, it may not capture all important aspects that patients may experience. OBJECTIVE: The aim of this collaboration was to develop an international consensus definition of low anterior resection syndrome that encompasses all aspects of the condition and is informed by all stakeholders. DESIGN: This international patient-provider initiative used an online Delphi survey, regional patient consultation meetings, and an international consensus meeting. PARTICIPANTS: Three expert groups participated: patients, surgeons, and other health professionals from 5 regions (Australasia, Denmark, Spain, Great Britain and Ireland, and North America) and in 3 languages (English, Spanish, and Danish). MAIN OUTCOME MEASURE: The primary outcome measured was the priorities for the definition of low anterior resection syndrome. RESULTS: Three hundred twenty-five participants (156 patients) registered. The response rates for successive rounds of the Delphi survey were 86%, 96%, and 99%. Eighteen priorities emerged from the Delphi survey. Patient consultation and consensus meetings refined these priorities to 8 symptoms and 8 consequences that capture essential aspects of the syndrome. LIMITATIONS: Sampling bias may have been present, in particular, in the patient panel because social media was used extensively in recruitment. There was also dominance of the surgical panel at the final consensus meeting despite attempts to mitigate this. CONCLUSIONS: This is the first definition of low anterior resection syndrome developed with direct input from a large international patient panel. The involvement of patients in all phases has ensured that the definition presented encompasses the vital aspects of the patient experience of low anterior resection syndrome. The novel separation of symptoms and consequences may enable greater sensitivity to detect changes in low anterior resection syndrome over time and with intervention