DPVis: Visual Analytics with Hidden Markov Models for Disease Progression Pathways

Clinical researchers use disease progression models to understand patient status and characterize progression patterns from longitudinal health records. One approach for disease progression modeling is to describe patient status using a small number of states that represent distinctive distributions over a set of observed measures. Hidden Markov models (HMMs) and its variants are a class of models that both discover these states and make inferences of health states for patients. Despite the advantages of using the algorithms for discovering interesting patterns, it still remains challenging for medical experts to interpret model outputs, understand complex modeling parameters, and clinically make sense of the patterns. To tackle these problems, we conducted a design study with clinical scientists, statisticians, and visualization experts, with the goal to investigate disease progression pathways of chronic diseases, namely type 1 diabetes (T1D), Huntington's disease, Parkinson's disease, and chronic obstructive pulmonary disease (COPD). As a result, we introduce DPVis which seamlessly integrates model parameters and outcomes of HMMs into interpretable and interactive visualizations. In this study, we demonstrate that DPVis is successful in evaluating disease progression models, visually summarizing disease states, interactively exploring disease progression patterns, and building, analyzing, and comparing clinically relevant patient subgroups.Comment: to appear at IEEE Transactions on Visualization and Computer Graphic

Data mining techniques for complex application domains

The emergence of advanced communication techniques has increased availability of large collection of data in electronic form in a number of application domains including healthcare, e- business, and e-learning. Everyday a large amount of records are stored electronically. However, finding useful information from such a large data collection is a challenging issue. Data mining technology aims automatically extracting hidden knowledge from large data repositories exploiting sophisticated algorithms. The hidden knowledge in the electronic data may be potentially utilized to facilitate the procedures, productivity, and reliability of several application domains. The PhD activity has been focused on novel and effective data mining approaches to tackle the complex data coming from two main application domains: Healthcare data analysis and Textual data analysis. The research activity, in the context of healthcare data, addressed the application of different data mining techniques to discover valuable knowledge from real exam-log data of patients. In particular, efforts have been devoted to the extraction of medical pathways, which can be exploited to analyze the actual treatments followed by patients. The derived knowledge not only provides useful information to deal with the treatment procedures but may also play an important role in future predictions of potential patient risks associated with medical treatments. The research effort in textual data analysis is twofold. On the one hand, a novel approach to discovery of succinct summaries of large document collections has been proposed. On the other hand, the suitability of an established descriptive data mining to support domain experts in making decisions has been investigated. Both research activities are focused on adopting widely exploratory data mining techniques to textual data analysis, which require overcoming intrinsic limitations for traditional algorithms for handling textual documents efficiently and effectively

Innovation and Standards in Clinical Practice: The Case of HIV Treatments

The goal of this study was to analyze the emergence of treatment standards associated with the adoption of anti-HIV drug innovations in the empirical setting of Italian clinical practice. Due to the rapid pace of technological change and the initial uncertainty concerning capabilities and indications of new treatments, the emergence of standard patterns of care turned out to be far from predictable and straightforward. Health providers' links to an international medicine and their internal coordination mechanisms were found to be associated with clinical decisions. Effectiveness and health costs of diverging treatment strategies were also compared.Medical innovation, Treatment standard, Clinical guidelines, HIV/AIDS, Sequence analysis

Knowledge, understanding and the dynamics of medical innovation

This paper investigates the processes by which scientific knowledge is created and legitimized. It focuses on scientific developments in a branch of medicine and explores the pathways through which the growth of knowledge enables advances in medical science and in clinical practice. This work draws conceptually on evolutionary approaches to technological change. The empirical part presents a longitudinal analysis of a database of scientific publications in the field of ophthalmology over a period of 50 years. Such an exercise allows us to identify pathways of shared understanding on a disease area, and to map out distinctive trajectories followed by the ophthalmology research community. The paper also contributes to general understanding of the innovation process by supporting the notion that knowledge coordination is a distributed process that cuts across and connects complementary areas of expertise.

Developmental Regulation of an Adhesin Gene during Cellular Morphogenesis in the Fungal Pathogen Candida albicans

Peer reviewedPublisher PD

Question design in nurse-led and GP-led telephone triage for same-day appointment requests: a comparative investigation

Objective: To compare doctors’ and nurses’ communication with patients in primary care telephone triage consultations. Design: Qualitative comparative study of content and form of questions in 51 telephone triage encounters between practitioners (general practitioners (GPs)=29; nurses=22) and patients requesting a same-day appointment in primary care. Audio-recordings of nurse-led calls were synchronised with video recordings of nurse's use of computer decision support software (CDSS) during triage. Setting: 2 GP practices in Devon and Warwickshire, UK. Participants: 4 GPs and 29 patients; and 4 nurses and 22 patients requesting a same-day face-to-face appointment with a GP. Main outcome measure: Form and content of practitioner-initiated questions and patient responses during clinical assessment. Results: A total of 484 question–response sequences were coded (160 GP; 324 N). Despite average call lengths being similar (GP=4 min, 37 s, (SD=1 min, 26 s); N=4 min, 39 s, (SD=2 min, 22 s)), GPs and nurses differed in the average number (GP=5.51, (SD=4.66); N=14.72, (SD=6.42)), content and form of questions asked. A higher frequency of questioning in nurse-led triage was found to be due to nurses’ use of CDSS to guide telephone triage. 89% of nurse questions were oriented to asking patients about their reported symptoms or to wider-information gathering, compared to 54% of GP questions. 43% of GP questions involved eliciting patient concerns or expectations, and obtaining details of medical history, compared to 11% of nurse questions. Nurses using CDSS frequently delivered questions designed as declarative statements requesting confirmation and which typically preferred a ‘no problem’ response. In contrast, GPs asked a higher proportion of interrogative questions designed to request information. Conclusions: Nurses and GPs emphasise different aspects of the clinical assessment process during telephone triage. These different styles of triage have implications for the type of information available following nurse-led or doctor-led triage, and for how patients experience triage

Salvage enzymes in nucleotide biosynthesis

Balanced pools of deoxyribonucleoside triphosphates (dNTPs), the building blocks of DNA, and ribonucleoside triphosphates (NTPs), the precursors of RNA, are crucial for a controlled cell proliferation. The dNTPs and NTPs are synthesized de novo via energy-consuming reactions involving low-weight molecules, and through a salvage pathway by recycling (deoxy)ribonucleosides originating from food and degraded DNA and RNA. The enzymes described in this thesis catalyze the first reaction in the salvage biosynthesis of dNTPs and NTPs. The crystal structures of three bacterial thymidine kinases (TKs) are described and the enzymes are investigated as potential targets for antibacterial therapies. TK is a deoxyribonucleoside kinase (dNK) with specificity for thymidine. In addition to the natural substrates, TK can also phosphorylate a number of nucleoside analogs used in antiviral and anticancer therapies. This thesis presents the structures of TKs from three pathogenic microorganisms: Ureaplasma urealyticum (parvum), Bacillus anthracis and Bacillus cereus, and compares them to the human thymidine kinase 1 (hTK1). The bacterial TKs and the hTK1 are structurally very similar and have a highly conserved active site architecture, which may complicate structure-based drug design. However, the different complex structures presented in this work provide information regarding the conformational changes of TK1-like enzymes during the time of reaction. The structure of human uridine-cytidine kinase 1 (UCK1) is also presented. Humans possess two uridine-cytidine kinases, UCK1 and UCK2. The expression pattern of these enzymes is tissue dependent, and despite high sequence as well as structural similarities they possess somewhat diverse substrate specificity. In addition to the natural substrates, uridine and cytidine, UCKs are able to phosphorylate a number of nucleoside analogs. The monomeric structure of UCK comprises four domains: a CORE domain, an NMP-binding domain, a LID domain and a β-hairpin domain, which upon substrate binding undergo dramatic conformational changes. In the structure described in this thesis the enzyme has been trapped in an intermediate conformation between a fully opened and fully closed form, which may represent a sequential mode of substrate binding

Multiple sclerosis: changes in microarchitecture of white matter tracts after training with a video game balance board

Purpose: To determine if high-intensity, task-oriented, visual feedback training with a video game balance board (Nintendo Wii) induces significant changes in diffusion-tensor imaging (DTI) parameters of cerebellar connections and other supratentorial associative bundles and if these changes are related to clinical improvement in patients with multiple sclerosis.Conclusion: Despite the low statistical power (35%) due to the small sample size, the results showed that training with the balance board system modified the microstructure of superior cerebellar peduncles. The clinical improvement observed after training might be mediated by enhanced myelinationrelated processes, suggesting that high-intensity, taskoriented exercises could induce favorable microstructural changes in the brains of patients with multiple sclerosis.Materials and Methods: The protocol was approved by local ethical committee; each participant provided written informed consent. In this 24-week, randomized, two-period crossover pilot study, 27 patients underwent static posturography and brain magnetic resonance (MR) imaging at study entry, after the first 12-week period, and at study termination. Thirteen patients started a 12-week training program followed by a 12-week period without any intervention, while 14 patients received the intervention in reverse order. Fifteen healthy subjects also underwent MR imaging once and underwent static posturography. Virtual dissection of white matter tracts was performed with streamline tractography; values of DTI parameters were then obtained for each dissected tract. Repeated measures analyses of variance were performed to evaluate whether DTI parameters significantly changed after intervention, with false discovery rate correction for multiple hypothesis testing.Results: There were relevant differences between patients and healthy control subjects in postural sway and DTI parameters (P <.05). Significant main effects of time by group interaction for fractional anisotropy and radial diffusivity of the left and right superior cerebellar peduncles were found (F2,23 range, 5.555-3.450; P = .036-.088 after false discovery rate correction). These changes correlated with objective measures of balance improvement detected at static posturography (r = 20.381 to 0.401, P < .05). However, both clinical and DTI changes did not persist beyond 12 weeks after training

The cultural epigenetics of psychopathology: The missing heritability of complex diseases found?

We extend a cognitive paradigm for gene expression based on the asymptotic limit theorems of information theory to the epigenetic epidemiology of mental disorders. In particular, we recognize the fundamental role culture plays in human biology, another heritage mechanism parallel to, and interacting with, the more familiar genetic and epigenetic systems. We do this via a model through which culture acts as another tunable epigenetic catalyst that both directs developmental trajectories, and becomes convoluted with individual ontology, via a mutually-interacting crosstalk mediated by a social interaction that is itself culturally driven. We call for the incorporation of embedding culture as an essential component of the epigenetic regulation of human mental development and its dysfunctions, bringing what is perhaps the central reality of human biology into the center of biological psychiatry. Current US work on gene-environment interactions in psychiatry must be extended to a model of gene-environment-culture interaction to avoid becoming victim of an extreme American individualism that threatens to create paradigms particular to that culture and that are, indeed, peculiar in the context of the world's cultures. The cultural and epigenetic systems of heritage may well provide the 'missing' heritability of complex diseases now under so much intense discussion