Addressing accuracy and precision issues in iTRAQ quantitation

iTRAQ (isobaric tags for relative or absolute quantitation) is a mass spectrometry technology that allows quantitative comparison of protein abundance by measuring peak intensities of reporter ions released from iTRAQ-tagged peptides by fragmentation during MS/MS. However, current data analysis techniques for iTRAQ struggle to report reliable relative protein abundance estimates and suffer with problems of precision and accuracy. The precision of the data is affected by variance heterogeneity: low signal data have higher relative variability; however, low abundance peptides dominate data sets. Accuracy is compromised as ratios are compressed toward 1, leading to underestimation of the ratio. This study investigated both issues and proposed a methodology that combines the peptide measurements to give a robust protein estimate even when the data for the protein are sparse or at low intensity. Our data indicated that ratio compression arises from contamination during precursor ion selection, which occurs at a consistent proportion within an experiment and thus results in a linear relationship between expected and observed ratios. We proposed that a correction factor can be calculated from spiked proteins at known ratios. Then we demonstrated that variance heterogeneity is present in iTRAQ data sets irrespective of the analytical packages, LC-MS/MS instrumentation, and iTRAQ labeling kit (4-plex or 8-plex) used. We proposed using an additive-multiplicative error model for peak intensities in MS/MS quantitation and demonstrated that a variance-stabilizing normalization is able to address the error structure and stabilize the variance across the entire intensity range. The resulting uniform variance structure simplifies the downstream analysis. Heterogeneity of variance consistent with an additive-multiplicative model has been reported in other MS-based quantitation including fields outside of proteomics; consequently the variance-stabilizing normalization methodology has the potential to increase the capabilities of MS in quantitation across diverse areas of biology and chemistry.

Reversibility of liver failure secondary to metastatic breast cancer by vinorelbine and cisplatin chemotherapy

Purpose: The development of liver metastases from breast cancer is associated with a very poor prognosis, estimated at 4 months median survival. Since treatment with many chemotherapeutic agents is relatively contraindicated, we assessed the safety, tolerability and potential efficacy of combination chemotherapy with vinorelbine and cisplatin (ViP). Method: Pilot study in 11 patients with histologically confirmed breast carcinoma, radiological evidence of liver metastases and serum bilirubin greater than 1.5 times the upper limit of normal. Patients received up to six cycles of cisplatin (75 mg/m 2) every 21 days and vinorelbine (20 mg/m 2) on days 1 and 8 of every 21-day cycle. Measurement of liver lesions was performed on CT scan every 8 weeks into treatment. Results: The most frequently reported adverse event was myelosuppression. Other adverse effects included nausea, vomiting and mild neurotoxicity. Two patients died after one treatment with ViP, one of whom suffered an intracerebral haemorrhage that was possibly treatment-related. Improvement in liver function tests was observed in 10 patients, and mean time to normalization of bilirubin levels was 36 days. Partial responses were documented radiologically in 7 out of 11 patients treated. Median overall survival from trial entry was 6.5 months (range 11-364 days), with one patient alive 13 months from trial entry. Conclusion: Normalization of liver function is possible with ViP treatment of metastatic breast cancer, offering the potential to prolong survival. Phase II clinical trials of this regimen in this patient group should include measurement of quality of life in order to assess risk versus benefit.

An evaluation of different features and learning models for anomalous event detection

The huge amount of CCTV footage available makes it very burdensome to process these videos manually through human operators. This has made automated processing of video footage through computer vision technologies necessary. During the past several years, there has been a large effort to detect abnormal activities through computer vision techniques. Typically, the problem is formulated as a novelty detection task where the system is trained on normal data and is required to detect events which do not fit the learned ‘normal’ model. There is no precise and exact definition for an abnormal activity; it is dependent on the context of the scene. Hence there is a requirement for different feature sets to detect different kinds of abnormal activities. In this work we evaluate the performance of different state of the art features to detect the presence of the abnormal objects in the scene. These include optical flow vectors to detect motion related anomalies, textures of optical flow and image textures to detect the presence of abnormal objects. These extracted features in different combinations are modeled using different state of the art models such as Gaussian mixture model(GMM) and Semi- 2D Hidden Markov model(HMM) to analyse the performances. Further we apply perspective normalization to the extracted features to compensate for perspective distortion due to the distance between the camera and objects of consideration. The proposed approach is evaluated using the publicly available UCSD datasets and we demonstrate improved performance compared to other state of the art methods.

Towards condition-invariant, top-down visual place recognition

In this paper we present a novel place recognition algorithm inspired by recent discoveries in human visual neuroscience. The algorithm combines intolerant but fast low resolution whole image matching with highly tolerant, sub-image patch matching processes. The approach does not require prior training and works on single images (although we use a cohort normalization score to exploit temporal frame information), alleviating the need for either a velocity signal or image sequence, differentiating it from current state of the art methods. We demonstrate the algorithm on the challenging Alderley sunny day – rainy night dataset, which has only been previously solved by integrating over 320 frame long image sequences. The system is able to achieve 21.24% recall at 100% precision, matching drastically different day and night-time images of places while successfully rejecting match hypotheses between highly aliased images of different places. The results provide a new benchmark for single image, condition-invariant place recognition.

Improving short utterance i-vector speaker verification using utterance variance modelling and compensation techniques

This paper proposes techniques to improve the performance of i-vector based speaker verification systems when only short utterances are available. Short-length utterance i-vectors vary with speaker, session variations, and the phonetic content of the utterance. Well established methods such as linear discriminant analysis (LDA), source-normalized LDA (SN-LDA) and within-class covariance normalisation (WCCN) exist for compensating the session variation but we have identified the variability introduced by phonetic content due to utterance variation as an additional source of degradation when short-duration utterances are used. To compensate for utterance variations in short i-vector speaker verification systems using cosine similarity scoring (CSS), we have introduced a short utterance variance normalization (SUVN) technique and a short utterance variance (SUV) modelling approach at the i-vector feature level. A combination of SUVN with LDA and SN-LDA is proposed to compensate the session and utterance variations and is shown to provide improvement in performance over the traditional approach of using LDA and/or SN-LDA followed by WCCN. An alternative approach is also introduced using probabilistic linear discriminant analysis (PLDA) approach to directly model the SUV. The combination of SUVN, LDA and SN-LDA followed by SUV PLDA modelling provides an improvement over the baseline PLDA approach. We also show that for this combination of techniques, the utterance variation information needs to be artificially added to full-length i-vectors for PLDA modelling.

Corneal confocal microscopy detects early nerve regeneration in diabetic neuropathy after simultaneous pancreas and kidney transplantation

Diabetic neuropathy is associated with increased morbidity and mortality. To date, limited data in subjects with impaired glucose tolerance and diabetes demonstrate nerve fiber repair after intervention. This may reflect a lack of efficacy of the interventions but may also reflect difficulty of the tests currently deployed to adequately assess nerve fiber repair, particularly in short-term studies. Corneal confocal microscopy (CCM) represents a novel noninvasive means to quantify nerve fiber damage and repair. Fifteen type 1 diabetic patients undergoing simultaneous pancreas-kidney transplantation (SPK) underwent detailed assessment of neurologic deficits, quantitative sensory testing (QST), electrophysiology, skin biopsy, corneal sensitivity, and CCM at baseline and at 6 and 12 months after successful SPK. At baseline, diabetic patients had a significant neuropathy compared with control subjects. After successful SPK there was no significant change in neurologic impairment, neurophysiology, QST, corneal sensitivity, and intraepidermal nerve fiber density (IENFD). However, CCM demonstrated significant improvements in corneal nerve fiber density, branch density, and length at 12 months. Normalization of glycemia after SPK shows no significant improvement in neuropathy assessed by the neurologic deficits, QST, electrophysiology, and IENFD. However, CCM shows a significant improvement in nerve morphology, providing a novel noninvasive means to establish early nerve repair that is missed by currently advocated assessment techniques.

Penal Culture and Hyperincarceration : the Revival of the Prison

What are the various forces influencing the role of the prison in late modern societies? What changes have there been in penality and use of the prison over the past 40 years that have led to the re-valorization of the prison? Using penal culture as a conceptual and theoretical vehicle, and Australia as a case study, this book analyses international developments in penality and imprisonment. Authored by some of Australia’s leading penal theorists, the book examines the historical and contemporary influences on the use of the prison, with analyses of colonialism, post colonialism, race, and what they term the ‘penal/colonial complex,’ in the construction of imprisonment rates and on the development of the phenomenon of hyperincarceration. The authors develop penal culture as an explanatory framework for continuity, change and difference in prisons and the nature of contested penal expansionism. The influence of transformative concepts such as ‘risk management’, ‘the therapeutic prison’, and ‘preventative detention’ are explored as aspects of penal culture. Processes of normalization, transmission and reproduction of penal culture are seen throughout the social realm. Comparative, contemporary and historical in its approach, the book provides a new analysis of penality in the 21st century.

Practical Advice to Entrepreneurs Series by ACE Adjunct Professor Dean Shepherd: Practical advice on learning the most from project failure

The author, Dean Shepherd, is of entrepreneurship—how entrepreneurs think, decide to act, and feel. He recently realized that while his publications in academic journals have implications for entrepreneurs, those implications have remained relatively hidden in the text of the articles and hidden in articles published in journals largely inaccessible to those involved in the entrepreneurial process. This series is designed to bring the practical implications of his research to the forefront.

Understanding the abnormal brain activity in epilepsy as a potential predictor of the onset of an epileptic seizure

The Brain Research Institute (BRI) uses various types of indirect measurements, including EEG and fMRI, to understand and assess brain activity and function. As well as the recovery of generic information about brain function, research also focuses on the utilisation of such data and understanding to study the initiation, dynamics, spread and suppression of epileptic seizures. To assist with the future focussing of this aspect of their research, the BRI asked the MISG 2010 participants to examine how the available EEG and fMRI data and current knowledge about epilepsy should be analysed and interpreted to yield an enhanced understanding about brain activity occurring before, at commencement of, during, and after a seizure. Though the deliberations of the study group were wide ranging in terms of the related matters considered and discussed, considerable progress was made with the following three aspects. (1) The science behind brain activity investigations depends crucially on the quality of the analysis and interpretation of, as well as the recovery of information from, EEG and fMRI measurements. A number of specific methodologies were discussed and formalised, including independent component analysis, principal component analysis, profile monitoring and change point analysis (hidden Markov modelling, time series analysis, discontinuity identification). (2) Even though EEG measurements accurately and very sensitively record the onset of an epileptic event or seizure, they are, from the perspective of understanding the internal initiation and localisation, of limited utility. They only record neuronal activity in the cortical (surface layer) neurons of the brain, which is a direct reflection of the type of electrical activity they have been designed to record. Because fMRI records, through the monitoring of blood flow activity, the location of localised brain activity within the brain, the possibility of combining fMRI measurements with EEG, as a joint inversion activity, was discussed and examined in detail. (3) A major goal for the BRI is to improve understanding about ``when'' (at what time) an epileptic seizure actually commenced before it is identified on an eeg recording, ``where'' the source of this initiation is located in the brain, and ``what'' is the initiator. Because of the general agreement in the literature that, in one way or another, epileptic events and seizures represent abnormal synchronisations of localised and/or global brain activity the modelling of synchronisations was examined in some detail. References C. M. Michel, G. Thut, S. Morand, A. Khateb, A. J. Pegna, R. Grave de Peralta, S. Gonzalez, M. Seeck and T. Landis, Electric source imaging of human brain functions, Brain Res. 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Recursive pathways to marginal likelihood estimation with prior-sensitivity analysis

We investigate the utility to computational Bayesian analyses of a particular family of recursive marginal likelihood estimators characterized by the (equivalent) algorithms known as "biased sampling" or "reverse logistic regression" in the statistics literature and "the density of states" in physics. Through a pair of numerical examples (including mixture modeling of the well-known galaxy dataset) we highlight the remarkable diversity of sampling schemes amenable to such recursive normalization, as well as the notable efficiency of the resulting pseudo-mixture distributions for gauging prior-sensitivity in the Bayesian model selection context. Our key theoretical contributions are to introduce a novel heuristic ("thermodynamic integration via importance sampling") for qualifying the role of the bridging sequence in this procedure, and to reveal various connections between these recursive estimators and the nested sampling technique.

Practical Advice for Entrepreneurs

I am interested in the psychology of entrepreneurship—how entrepreneurs think, decide to act, and feel. I recently realized that while my publications in academic journals have implications for entrepreneurs, those implications have remained relatively hidden in the text of the articles and hidden in articles published in journals largely inaccessible to those involved in the entrepreneurial process. This book is designed to bring the practical implications of my research to the forefront. I decided to take a different approach with this book and not write it for a publisher. I did this because I wanted the ideas to be freely available: (1) I wanted those interested in practical advice for entrepreneurs to be able to freely download, distribute, and use this information (I only ask that the content be properly cited), (2) I wanted to release the chapters independently and make chapters available as they are finished, and; (3) I wanted this work to be a dialogue rather than a one-way conversation—I hope readers email me feedback (positive and negative) so that I can use this information to revise the book. In producing the journal articles underpinning this book, I have had the pleasure of working with many talented and wonderful colleagues—they are cited at the end of each chapter. I hope you find some of the advice in this book useful.

Overview of the ShARe/CLEF eHealth Evaluation Lab 2014

This paper reports on the 2nd ShARe/CLEFeHealth evaluation lab which continues our evaluation resource building activities for the medical domain. In this lab we focus on patients' information needs as opposed to the more common campaign focus of the specialised information needs of physicians and other healthcare workers. The usage scenario of the lab is to ease patients and next-of-kins' ease in understanding eHealth information, in particular clinical reports. The 1st ShARe/CLEFeHealth evaluation lab was held in 2013. This lab consisted of three tasks. Task 1 focused on named entity recognition and normalization of disorders; Task 2 on normalization of acronyms/abbreviations; and Task 3 on information retrieval to address questions patients may have when reading clinical reports. This year's lab introduces a new challenge in Task 1 on visual-interactive search and exploration of eHealth data. Its aim is to help patients (or their next-of-kin) in readability issues related to their hospital discharge documents and related information search on the Internet. Task 2 then continues the information extraction work of the 2013 lab, specifically focusing on disorder attribute identification and normalization from clinical text. Finally, this year's Task 3 further extends the 2013 information retrieval task, by cleaning the 2013 document collection and introducing a new query generation method and multilingual queries. De-identified clinical reports used by the three tasks were from US intensive care and originated from the MIMIC II database. Other text documents for Tasks 1 and 3 were from the Internet and originated from the Khresmoi project. Task 2 annotations originated from the ShARe annotations. For Tasks 1 and 3, new annotations, queries, and relevance assessments were created. 50, 79, and 91 people registered their interest in Tasks 1, 2, and 3, respectively. 24 unique teams participated with 1, 10, and 14 teams in Tasks 1, 2 and 3, respectively. The teams were from Africa, Asia, Canada, Europe, and North America. The Task 1 submission, reviewed by 5 expert peers, related to the task evaluation category of Effective use of interaction and targeted the needs of both expert and novice users. The best system had an Accuracy of 0.868 in Task 2a, an F1-score of 0.576 in Task 2b, and Precision at 10 (P@10) of 0.756 in Task 3. The results demonstrate the substantial community interest and capabilities of these systems in making clinical reports easier to understand for patients. The organisers have made data and tools available for future research and development.

Dapsone-induced agranulocytosis. The role of xenobiotic-metabolizing enzymes demonstrated by a case report [Dapson-induzierte Agranulozytose]

A 34-year-old female patient with a three year history of generalized granuloma annulare was treated systemically with dapsone (DADPS). Six weeks after the onset of treatment, the patient developed an extensive tonsillitis of the base of the tongue with fever and malaise. Routine laboratory work showed a leukocytopenia with agranulocytosis. Further investigation revealed a marked decrease of the enzyme activity of N-acetyltransferase 2, which plays an important role in dapsone metabolism. Treatment included the cessation of dapsone, antibiotic coverage, and G-CSF leading to the rapid improvement of symptoms and normalization of leukocyte counts. Dapsone-induced angina agranulocytotica is a rare event and is interpreted as an idiosyncratic reaction. Depending on genetic polymorphisms of various enzymes, dapsone can be metabolized to immunologically or toxicologically relevant intermediates. Because of the risk of severe hematologic reactions, dapsone should only be employed for solid indications and with appropriate monitoring. [Article in German]

Supporting residents’ expression of sexuality : the initial construction of a sexuality assessment tool for residential aged care facilities

Background: Sexuality is a key component of quality of life and well-being and a need to express one’s sexuality continues into old age. Staff and families in residential aged care facilities often find expressions of sexuality by residents, particularly those living with dementia, challenging and facilities often struggle to address individuals’ needs in this area. This paper describes the development of an assessment tool which enables residential aged care facilities to identify how supportive their organisation is of all residents’ expression of their sexuality, and thereby improve where required. Methods: Multi-phase design using qualitative methods and a Delphi technique. Tool items were derived from the literature and verified by qualitative interviews with aged care facility staff, residents and families. The final item pool was confirmed via a reactive Delphi process. Results: A final item pool of sixty-nine items grouped into seven key areas allows facilities to score their compliance with the areas identified as being supportive of older people’s expression of their sexuality in a residential aged care environment. Conclusions: The sexuality assessment tool (SexAT) guides practice to support the normalization of sexuality in aged care homes and assists facilities to identify where enhancements to the environment, policies, procedures and practices, information and education/training are required. The tool also enables facilities to monitor initiatives in these areas over time.

Development of a new index of balance in adults with intellectual and developmental disabilities

Purposes: The first objective was to propose a new model representing the balance level of adults with intellectual and developmental disabilities (IDD) using Principal Components Analysis (PCA); and the second objective was to use the results from the PCA recorded by regression method to construct and validate summative scales of the standardized values of the index, which may be useful to facilitate a balance assessment in adults with IDD. Methods: A total of 801 individuals with IDD (509 males) mean 33.1±8.5 years old, were recruited from Special Olympic Games in Spain 2009 to 2012. The participants performed the following tests: the timed-stand test, the single leg stance test with open and closed eyes, the Functional Reach Test, the Expanded Timed-Get-up-and-Go Test. Data was analyzed using principal components analysis (PCA) with Oblimin rotation and Kaiser normalization. We examined the construct validity of our proposed two-factor model underlying balance for adults with IDD. The scores from PCA were recorded by regression method and were standardized. Results: The Component Plot and Rotated Space indicated that a two-factor solution (Dynamic and Static Balance components) was optimal. The PCA with direct Oblimin rotation revealed a satisfactory percentage of total variance explained by the two factors: 51.6 and 21.4%, respectively. The median score standardized for component dynamic and static of the balance index for adults with IDD is shown how references values. Conclusions: Our study may lead to improvements in the understanding and assessment of balance in adults with IDD. First, it confirms that a two-factor model may underlie the balance construct, and second, it provides an index that may be useful for identifying the balance level for adults with IDD.