The Role of Free/Libre and Open Source Software in Learning Health Systems

OBJECTIVE: To give an overview of the role of Free/Libre and Open Source Software (FLOSS) in the context of secondary use of patient data to enable Learning Health Systems (LHSs). METHODS: We conducted an environmental scan of the academic and grey literature utilising the MedFLOSS database of open source systems in healthcare to inform a discussion of the role of open source in developing LHSs that reuse patient data for research and quality improvement. RESULTS: A wide range of FLOSS is identified that contributes to the information technology (IT) infrastructure of LHSs including operating systems, databases, frameworks, interoperability software, and mobile and web apps. The recent literature around the development and use of key clinical data management tools is also reviewed. CONCLUSIONS: FLOSS already plays a critical role in modern health IT infrastructure for the collection, storage, and analysis of patient data. The nature of FLOSS systems to be collaborative, modular, and modifiable may make open source approaches appropriate for building the digital infrastructure for a LHS.</p

Distinguishing low frequency mutations from RT-PCR and sequence errors in viral deep sequencing data

There is a high prevalence of coronary artery disease (CAD) in patients with left bundle branch block (LBBB); however there are many other causes for this electrocardiographic abnormality. Non-invasive assessment of these patients remains difficult, and all commonly used modalities exhibit several drawbacks. This often leads to these patients undergoing invasive coronary angiography which may not have been necessary. In this review, we examine the uses and limitations of commonly performed non-invasive tests for diagnosis of CAD in patients with LBBB

A robust Bayesian analysis of the impact of policy decisions on crop rotations.

We analyse the impact of a policy decision on crop rotations, using the imprecise land use model that was developed by the authors in earlier work. A specific challenge in crop rotation models is that farmer’s crop choices are driven by both policy changes and external non-stationary factors, such as rainfall, temperature and agricultural input and output prices. Such dynamics can be modelled by a non-stationary stochastic process, where crop transition probabilities are multinomial logistic functions of such external factors. We use a robust Bayesian approach to estimate the parameters of our model, and validate it by comparing the model response with a non-parametric estimate, as well as by cross validation. Finally, we use the resulting predictions to solve a hypothetical yet realistic policy problem

Randomised field trial to evaluate serological response after foot-and-mouth disease vaccination in Turkey

AbstractDespite years of biannual mass vaccination of cattle, foot-and-mouth disease (FMD) remains uncontrolled in Anatolian Turkey. To evaluate protection after mass vaccination we measured post-vaccination antibodies in a cohort of cattle (serotypes O, A and Asia-1). To obtain results reflecting typical field protection, participants were randomly sampled from across Central and Western Turkey after routine vaccination. Giving two-doses one month apart is recommended when cattle are first vaccinated against FMD. However, due to cost and logistics, this is not routinely performed in Turkey, and elsewhere. Nested within the cohort, we conducted a randomised trial comparing post-vaccination antibodies after a single-dose versus a two-dose primary vaccination course.Four to five months after vaccination, only a third of single-vaccinated cattle had antibody levels above a threshold associated with protection. A third never reached this threshold, even at peak response one month after vaccination. It was not until animals had received three vaccine doses in their lifetime, vaccinating every six months, that most (64% to 86% depending on serotype) maintained antibody levels above this threshold. By this time cattle would be >20 months old with almost half the population below this age. Consequently, many vaccinated animals will be unprotected for much of the year. Compared to a single-dose, a primary vaccination course of two-doses greatly improved the level and duration of immunity. We concluded that the FMD vaccination programme in Anatolian Turkey did not produce the high levels of immunity required. Higher potency vaccines are now used throughout Turkey, with a two-dose primary course in certain areas.Monitoring post-vaccination serology is an important component of evaluation for FMD vaccination programmes. However, consideration must be given to which antigens are present in the test, the vaccine and the field virus. Differences between these antigens affect the relationship between antibody titre and protection

An investigation of factual and counterfactual feedback information in early visual cortex

Primary visual cortex receives approximately 90% of the input to the retina, however this only accounts for around 5% of the input to V1 (Muckli, 2010). The majority of the input to V1 is in fact from other cortical and sub-cortical parts of the brain that arrive there via lateral and feedback pathways. It is therefore critical to our knowledge of visual perception to understand how these feedback responses influence visual processing. The aim of this thesis is to investigate different sources of non-visual feedback to early visual cortex. To do this we use a combination of an occlusion paradigm, derived from F. W. Smith and Muckli (2010), and functional magnetic resonance imagining. Occlusion offers us a method to inhibit the feedforward flow of information to the retina from a specific part of the visual field. By inhibiting the feedforward information we exploit the highly precise retinotopic organisation of visual cortex by rendering a corresponding patch of cortex free of feedforward input. From this isolated patch of cortex we can ask questions about the information content of purely feedback information. In Chapter 3 we investigated whether or not information about valance was present in non-stimulated early visual cortex. We constructed a 900 image set that contained an equal number of images for neutral, positive and negative valance across animal, food and plant categories. We used an m-sequence design to allow us to present image set within a standard period of time for fMRI. We were concerned about low-level image properties being a potential confound, so a large image set would allow us to average out these low-level properties. We occluded the lower-right quadrant of each image and presented each image only once to our subjects. The image set was rated for valance and arousal after fMRI so that individual subjectivity could be accounted for. We used multivariate pattern analysis (MVPA) to decode pairs of neutral, positive and negative valance. We found that in both stimulated and non-stimulated V1, V2 and V3, and the amygdala and pulvinar only information about negative valance could be decoded. In a second analysis we again used MVPA to cross-decode between pairs of valance and category. By training the classifier on pairs of valance that each contained two categories, we could ask the question of whether the classifier generalises to the left out category for the same pair of valance. We found that valance does generalise across category in both stimulated and non-stimulated cortex, and in the amygdala and pulvinar. These results demonstrate that information about valance, particularly negative valance, is represented in low level visual areas and is generalisable across animal, food and plant categories. In Chapter 4 we explored the retinotopic organisation of object and scene sound responses in non-stimulated early visual cortex. We embedded a repeating object sound (axe chopping or motor starting) in to a scene sound (blizzard wind or forest) and used MVPA to read out object or scene information from non-stimulated early visual cortex. We found that object sounds were decodable in the fovea and scene sounds were decodable in the periphery. This finding demonstrates that auditory feedback to visual cortex has an eccentricity bias corresponding to the functional role involved. We suggest that object information feeds back to the fovea for fine-scaled discrimination whereas abstract information feeds back to the periphery to provide a modulatory contextual template for vision. In a second experiment in Chapter 4 we further explored the similarity between categorical representations between sound and video stimuli in non-stimulated early visual cortex. We use video stimuli and separate the audio and visual parts in to unimodal stimuli. We occlude the bottom right quadrant of the videos and use MVPA to cross-decode between sounds and videos (and vice-versa) from responses in occluded cortex. We find that a classifier trained on one modality can decode the other in occluded cortex. This finding tells us that there is an overlap in the neural representation of aural and visual stimuli in early visual cortex. In Chapter 5 we probe the internal thought processes of subjects after occluding a short video sequence. We use a priming sequence to generate predictions as subjects are asked to imagine how events from a video unfold during occlusion. We then probe these predictions with a series of test frames corresponding to points in time, either close in time to the offset of the video, just before the video would be expected to reappear, the matching frame from when the video would be expected to reappear or a frame from the very distant future. In an adaption paradigm we find that predictions best match the test frames around the point in time that subjects expect the video to reappear. The test frame from a point close in time to the offset of the video was rarely a match. This tells us that the predictions that subjects make are not related to the offset of the priming sequence but represent a future state of the world that they have not seen. In a second control experiment we show that these predictions are absent when the priming sequence is randomised, and that predictions take between 600ms and 1200ms to fully develop. These findings demonstrate the dynamic flexibility of internal models, that information about these predictions can be read out in early visual cortex and that stronger representations form if given additional time. In Chapter 6 we again probe at internal dynamic predictions by using virtual navigation paradigm. We use virtual reality to train subjects in a new environment where they can build strong representations of four categorical rooms (kitchen, bedroom, office and game room). Later in fMRI we provide subjects with a direction cue and a starting room and ask them to predict the upcoming room by combining the information. The starting room is shown as a short video clip with the bottom right quadrant occluded. During the video sequence of the starting room, we find that we can read out information about the future room from non-stimulated early visual cortex. In a second control experiment, when we remove the direction cue information about the future room can no longer be decoded. This finding demonstrates that dynamic predictions about the immediate future are present in early visual cortex during simultaneous visual stimulation and that we can read out these predictions with 3T fMRI. These findings increase our knowledge about the types of non-visual information available to early visual cortical areas and provide insight in to the influence they have on vision. These results lend support to the idea that early visual areas may act as a blackboard for read and write operations for communication around the brain (Muckli et al., 2015; Mumford, 1991; Murray et al., 2016; Roelfsema & de Lange, 2016; Williams et al., 2008). Current models of predictive coding will need to be updated to account for the brains ability to switch between two different processing streams, one that is factual and related to an external stimulus and one that is stimulus independent and internal

An investigation into some aspects of the thin layer chromatographic assay of Pregnanediol with emphasis on the suitability of this method as a clinical laboratory routine

Pregnanediol (5B Pregnane- 3⋉- 20⋉- dial) is the chief urinary metabolite of progesterone, and as such is important in that variations in its concentration reflect variations in progesterone secretion. Estimations of pregnanediol concentration are therefore of considerable interest to the obstetrician and gynaecologist. Pregnanediol was first identified in the urine of pregnant women in 1929 by Marrian. Nearly ten years later Venning developed a method by which the glucuronic acid ester of pregnanediol could be extracted from the urine and its concentration gravimetrically determined. Numerous variations of the Venning theme were published in the next few years, each being claimed by its authors to be an improvement on the original. Most of these involved the estimation of the conjugated form, and it was a while before the advantage of estimating the hydrolysed aglycone was realized. Hydrolysis, when it was practised, resolved itself into two methods - namely, hydrolysis by heating the urine with a mineral acid, and enzymic hydrolysis by incubation with beta-glucuronidase. Acid hydrolysis, while producing a less clean hydrolysate, is more rapid and convenient than enzyme hydrolysis, and is used in the Klapper method which is presently the most widely used method in clinical studies. Klapper employs a double chromategraphic column separation of pregnanediol followed by colorimetric evaluation. Variations of Klapper's method have also appeared and not a few investigators have published comparisons of the various methods. Klapper himself compared his method to certain other methods and concluded that his was definitely superior. Of the accuracy of the Klapper method there is no doubt. Subsequent methods have proved more sensitive, but in terms of practicability Klapper's is the method of choice. As was pointed out with some complacency, "practicability is most satisfactory, one technician readily performing some twenty determinations in one week." In contrast to the flood of criticisms, comparisons, variations, claims and counter-claims which accompanied the publication of the abovementioned methods, the thin layer chromatographic method perfected by Waldi attracted very little attention. It is very much more rapid than all other existing techniques, is very sensitive, specific and of acceptable accuracy. In an attempt to ensure its usefulness for clinical and medical research laboratories, the Waldi method has been marketed in 'kit' form. It is intended primarily as a diagnostic aid in establishing pregnancy, and as such it might have enjoyed considerable application had it not been for the advent of the immunological method of pregnancy diagnosis which is very much more rapid. Nevertheless, the Waldi method, used purely as a means of assessing the pregnanediol content of the urine is extremely useful, and it is the purpose of this investigation to establish this usefulness, especially with respect to routine clinical investigations. The validity of some diagnoses which are based on pregnanediol assay results, is also investigated. As it is impossible to explain the significance or usefulness of a pregnanediol assay without first explaining the functions of progesterone, some time and space must be expended in a brief description, firstly, of the role played by progesterone in the phenomenon of the menstrual cycle, and secondly, of its vital importance in pregnancy. It must be realized that progesterone is only one of the many hormones involved in these events, but, in order to limit the introduction of extraneous detail, no mention is made of the other hormonal participants except when necessary for the understanding of the whole. It may be mentioned here that much of the evidence that was used for the elucidation of the functions and origins of progesterone, was derived from studies of its metabolite, pregnanediol

Understanding tsunami warning systems

The eastern Australian coastline faces some 8000km of active tectonic plate boundary that is capable of generating a tsunami thatcould reach Australia in two to four hours. This makes it imperative that coastal communities understand and can respond effectively to the Australian Tsunami Warning System. Activation of this warning system could result in warning times ranging from 90 minutes to three hours. Warning times of these durations could leave insufficient time for people to implement their emergency plan (e.g., to prepare their property, plan an evacuation etc.) on receipt of a warning. This project is researching key aspects of community response capability