Construction and evaluation of classifiers for forensic document analysis

In this study we illustrate a statistical approach to questioned document examination. Specifically, we consider the construction of three classifiers that predict the writer of a sample document based on categorical data. To evaluate these classifiers, we use a data set with a large number of writers and a small number of writing samples per writer. Since the resulting classifiers were found to have near perfect accuracy using leave-one-out cross-validation, we propose a novel Bayesian-based cross-validation method for evaluating the classifiers.Comment: Published in at http://dx.doi.org/10.1214/10-AOAS379 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

MINRES-QLP: a Krylov subspace method for indefinite or singular symmetric systems

CG, SYMMLQ, and MINRES are Krylov subspace methods for solving symmetric systems of linear equations. When these methods are applied to an incompatible system (that is, a singular symmetric least-squares problem), CG could break down and SYMMLQ's solution could explode, while MINRES would give a least-squares solution but not necessarily the minimum-length (pseudoinverse) solution. This understanding motivates us to design a MINRES-like algorithm to compute minimum-length solutions to singular symmetric systems. MINRES uses QR factors of the tridiagonal matrix from the Lanczos process (where R is upper-tridiagonal). MINRES-QLP uses a QLP decomposition (where rotations on the right reduce R to lower-tridiagonal form). On ill-conditioned systems (singular or not), MINRES-QLP can give more accurate solutions than MINRES. We derive preconditioned MINRES-QLP, new stopping rules, and better estimates of the solution and residual norms, the matrix norm, and the condition number.Comment: 26 pages, 6 figure

Calcium channel blockers and breast cancer incidence: An updated systematic review and meta-analysis of the evidence

Controversy exists regarding the potential association between taking calcium channel blockers (CCBs) and the development of breast cancer. As a positive association would have important public health implications due to the widespread use of CCBs, this study aimed to incorporate new evidence to determine whether an association is likely to exist. We searched MEDLINE, EMBASE and the Cochrane Library to 28 June 2016 for relevant literature. References and citing articles were checked and authors contacted as necessary. Two authors independently selected articles and extracted data. Twenty-nine studies were reviewed; 26 were non-randomised studies (NRS). Meta-analysis of study data where adjustment for ‘confounding by indication’ was judged to be present suggests that an association, if any, is likely to be modest in magnitude (pooled odds/risk ratio 1.09 (95% confidence interval (CI) 1.03–1.15, I 2 = 0%, 8 sub-studies; pooled hazard ratio 0.99 (95% CI 0.94–1.03, I 2 = 35%, 9 sub-studies)). There are credible study data showing an increased relative risk with long-term use of CCBs, but the results of our meta-analysis and of meta-regression of log relative risk against minimum follow-up time are mixed. The current summative evidence does not support a clear association between taking CCBs and developing breast cancer. However, uncertainty remains, especially for long-term use and any association might not be uniform between different populations and/or breast cancer sub-types. We t hus recommend further NRS in settings where CCB use is highly prevalent and population-based cancer, prescription and health-registries exist, to resolve this continuing uncertainty. PROSPERO, CRD42015026712

An AICD-based functional screen to identify APP metabolism regulators

<p>Abstract</p> <p>Background</p> <p>A central event in Alzheimer's disease (AD) is the regulated intramembraneous proteolysis of the β-amyloid precursor protein (APP), to generate the β-amyloid (Aβ) peptide and the APP intracellular domain (AICD). Aβ is the major component of amyloid plaques and AICD displays transcriptional activation properties. We have taken advantage of AICD transactivation properties to develop a genetic screen to identify regulators of APP metabolism. This screen relies on an APP-Gal4 fusion protein, which upon normal proteolysis, produces AICD-Gal4. Production of AICD-Gal4 induces Gal4-UAS driven luciferase expression. Therefore, when regulators of APP metabolism are modulated, luciferase expression is altered.</p> <p>Results</p> <p>To validate this experimental approach we modulated α-, β-, and γ-secretase levels and activities. Changes in AICD-Gal4 levels as measured by Western blot analysis were strongly and significantly correlated to the observed changes in AICD-Gal4 mediated luciferase activity. To determine if a known regulator of APP trafficking/maturation and Presenilin1 endoproteolysis could be detected using the AICD-Gal4 mediated luciferase assay, we knocked-down Ubiquilin 1 and observed decreased luciferase activity. We confirmed that Ubiquilin 1 modulated AICD-Gal4 levels by Western blot analysis and also observed that Ubiquilin 1 modulated total APP levels, the ratio of mature to immature APP, as well as PS1 endoproteolysis.</p> <p>Conclusion</p> <p>Taken together, we have shown that this screen can identify known APP metabolism regulators that control proteolysis, intracellular trafficking, maturation and levels of APP and its proteolytic products. We demonstrate for the first time that Ubiquilin 1 regulates APP metabolism in the human neuroblastoma cell line, SH-SY5Y.</p

Trajectories of depression and anxiety symptom severity during psychological therapy for common mental health problems

BACKGROUND: There is substantial variation in patient symptoms following psychological therapy for depression and anxiety. However, reliance on endpoint outcomes ignores additional interindividual variation during therapy. Knowing a patient's likely symptom trajectories could guide clinical decisions. We aimed to identify latent classes of patients with similar symptom trajectories over the course of psychological therapy and explore associations between baseline variables and trajectory class. METHODS: Patients received high-intensity psychological treatment for common mental health problems at National Health Service Improving Access to Psychological Therapies services in South London (N = 16 258). To identify trajectories, we performed growth mixture modelling of depression and anxiety symptoms over 11 sessions. We then ran multinomial regressions to identify baseline variables associated with trajectory class membership. RESULTS: Trajectories of depression and anxiety symptoms were highly similar and best modelled by four classes. Three classes started with moderate-severe symptoms and showed (1) no change, (2) gradual improvement, and (3) fast improvement. A final class (4) showed initially mild symptoms and minimal improvement. Within the moderate-severe baseline symptom classes, patients in the two showing improvement as opposed to no change tended not to be prescribed psychotropic medication or report a disability and were in employment. Patients showing fast improvement additionally reported lower baseline functional impairment on average. CONCLUSIONS: Multiple trajectory classes of depression and anxiety symptoms were associated with baseline characteristics. Identifying the most likely trajectory for a patient at the start of treatment could inform decisions about the suitability and continuation of therapy, ultimately improving patient outcomes

All clinically-relevant blood components transmit prion disease following a single blood transfusion: a sheep model of vCJD

Variant CJD (vCJD) is an incurable, infectious human disease, likely arising from the consumption of BSE-contaminated meat products. Whilst the epidemic appears to be waning, there is much concern that vCJD infection may be perpetuated in humans by the transfusion of contaminated blood products. Since 2004, several cases of transfusion-associated vCJD transmission have been reported and linked to blood collected from pre-clinically affected donors. Using an animal model in which the disease manifested resembles that of humans affected with vCJD, we examined which blood components used in human medicine are likely to pose the greatest risk of transmitting vCJD via transfusion. We collected two full units of blood from BSE-infected donor animals during the pre-clinical phase of infection. Using methods employed by transfusion services we prepared red cell concentrates, plasma and platelets units (including leucoreduced equivalents). Following transfusion, we showed that all components contain sufficient levels of infectivity to cause disease following only a single transfusion and also that leucoreduction did not prevent disease transmission. These data suggest that all blood components are vectors for prion disease transmission, and highlight the importance of multiple control measures to minimise the risk of human to human transmission of vCJD by blood transfusion

Cost analysis and outcomes of endoscopic, minimal access and open pancreatic necrosectomy.

To assess both individual patient and institutional costs as well as outcomes in patients with pancreatic necrosis who underwent either endoscopic, minimal access or open pancreatic necrosectomy. These data can be used to evaluate clinical effectiveness with a view to informing local health care providers. Intervention for infected pancreatic necrosis is associated with a high morbidity, mortality and long hospital stays. Minimal access surgical step-up approaches have been the gold standard of care, however endoscopic approaches are now offered preferentially. All patients undergoing endoscopic (EN), minimal access retroperitoneal (MARPN) and open (OPN) necrosectomy at a single institution from April 2015-March 2017 were included. Patients were selected for intervention based on morphology and position of the necrosis and on clinical factors. Patient level costing systems were used to determine inpatient and outpatient costs. 86 patients were included: 38 underwent EN, 35 MARPN and 13 OPN. Pre-operative APACHEII was 6 vs 9 vs 9 (p=0.017) and CRP 107 vs 204 vs 278, (p=0.012), respectively. Post-operative stay was 19 days for EN vs. 41 for MARPN vs. 42 for OPN (p=0.007). Complications occurred in 68.4%, 68.6% and 46.2% (p=0.298) while mortality was 10.5%, 22.9% and 15.4% (p=0.379) respectively. Mean total cost was £31,364 for EN, £52,770 for MARPN (p=0.008) and £60,346 for OPN. Ward and critical care costs for EN were lower than for MARPN (ward: £9,430 vs. £14,033, p=0.024; critical care: £5,317 vs. £16,648, p=0.056)

Multiple breath washout in bronchiectasis clinical trials:is it feasible?

Background: Evaluation of Multiple Breath Washout (MBW) set-up including staff training, certification and central “over-reading” for data quality control is essential to determine the feasibility of MBW in future bronchiectasis studies. Aims: To assess the outcomes of a MBW training, certification and central over-reading programme. Methods: MBW training and certification was conducted in European sites collecting LCI data in the BronchUK clinimetrics and/or i-BEST-1 studies. The blended training programme included the use of an eLearning tool and a 1-day face-to-face session. Sites submitted MBW data to trained central over-readers who determined validity and quality. Results: Thirteen training days were delivered to 56 participants from 22 sites. 18/22 (82%) were MBW naïve. Participant knowledge and confidence increased significantly (p<0.001). By the end of the study recruitment, 15/22 sites (68%) had completed certification with a mean (range) time since training of 6.2 (3-14) months. In the BronchUK clinimetrics study, 468/589 (79%) tests met45 the quality criteria following central over-reading, compared with 137/236 (58%) tests in the i-BEST-1 study. Conclusions: LCI is feasible in a bronchiectasis multicentre clinical trial setting however, consideration of site experience in terms of training as well as assessment of skill drift and the need for re-training may be important to reduce time to certification and optimise data quality. Longer times to certification, a higher percentage of naive sites and patients with worse lung function may have contributed to the lower success rate in the i-BEST-1 study

Channel choice complications:Exploring the multiplex nature of citizens' channel choices

Part 2: E-Government Services and Open GovernmentInternational audienceIn spite of massive investment and increased adoption of digital services, citizens continue to use traditional channels to interact with public organizations. The channel choice (CC) field of research tries to understand citizens’ interactions with public authorities to make the interaction more efficient and increase citizen satisfaction. However, most studies have been conducted either as surveys of hypothetical services or in experimental settings, leading to a lack of empirical data from actual use contexts. Therefore, we present the results of a sequential mixed methods study which combines observations of citizen-caseworker interaction in a call center, contextual interviews with callers, and a survey classifying topics from 10,000 telephone calls. We contribute to the CC field and practice with rich empirical data from studies of actual channel choices. Specifically, the study explores the multiplex nature of real-life CC and demonstrate how telephone calls can be part of a process, which occurs across both traditional and digital channels. Moreover, we identify problems, which cause telephone calls related to digital services, and classify these in two groups: information related problems and action related problems

Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease

Background Prostate cancer (PrCa) demonstrates a heterogeneous clinical presentation ranging from largely indolent to lethal. We sought to identify a signature of rare inherited variants that distinguishes between these two extreme phenotypes. Methods We sequenced germline whole exomes from 139 aggressive (metastatic, age of diagnosis < 60) and 141 non-aggressive (low clinical grade, age of diagnosis ≥60) PrCa cases. We conducted rare variant association analyses at gene and gene set levels using SKAT and Bayesian risk index techniques. GO term enrichment analysis was performed for genes with the highest differential burden of rare disruptive variants. Results Protein truncating variants (PTVs) in specific DNA repair genes were significantly overrepresented among patients with the aggressive phenotype, with BRCA2, ATM and NBN the most frequently mutated genes. Differential burden of rare variants was identified between metastatic and non-aggressive cases for several genes implicated in angiogenesis, conferring both deleterious and protective effects. Conclusions Inherited PTVs in several DNA repair genes distinguish aggressive from non-aggressive PrCa cases. Furthermore, inherited variants in genes with roles in angiogenesis may be potential predictors for risk of metastases. If validated in a larger dataset, these findings have potential for future clinical application