Outperformance in exchange-traded fund pricing deviations: Generalized control of data snooping bias

An investigation into exchange-traded fund (ETF) outperforrnance during the period 2008-2012 is undertaken utilizing a data set of 288 U.S. traded securities. ETFs are tested for net asset value (NAV) premium, underlying index and market benchmark outperformance, with Sharpe, Treynor, and Sortino ratios employed as risk-adjusted performance measures. A key contribution is the application of an innovative generalized stepdown procedure in controlling for data snooping bias. We find that a large proportion of optimized replication and debt asset class ETFs display risk-adjusted premiums with energy and precious metals focused funds outperforming the S&P 500 market benchmark. 

Colorectal cancer risk following adenoma removal: a large prospective population-based cohort study

Background: Randomised controlled trials have demonstrated significant reductions in colorectal cancer (CRC) incidence and mortality associated with polypectomy. However, little is known about whether polypectomy is effective at reducing CRC risk in routine clinical practice. The aim of this investigation was to quantify CRC risk following polypectomy in a large prospective population-based cohort study.

Methods: Patients with incident colorectal polyps between 2000 and 2005 in Northern Ireland (NI) were identified via electronic pathology reports received to the NI Cancer Registry (NICR). Patients were matched to the NICR to detect CRC and deaths up to 31st December 2010. CRC standardised incidence ratios (SIRs) were calculated and Cox proportional hazards modelling applied to determine CRC risk.

Results: During 44,724 person-years of follow-up, 193 CRC cases were diagnosed amongst 6,972 adenoma patients, representing an annual progression rate of 0.43%. CRC risk was significantly elevated in patients who had an adenoma removed (SIR 2.85; 95% CI: 2.61 to 3.25) compared with the general population. Male sex, older age, rectal site and villous architecture were associated with an increased CRC risk in adenoma patients. Further analysis suggested that not having a full colonoscopy performed at, or following, incident polypectomy contributed to the excess CRC risk.

Conclusions: CRC risk was elevated in individuals following polypectomy for adenoma, outside of screening programmes.

Impact: This finding emphasises the need for full colonoscopy and adenoma clearance, and appropriate surveillance, after endoscopic diagnosis of adenoma.

Prevalence, Nature, Severity and Risk Factors for Prescribing Errors in Hospital Inpatients: Prospective Study in 20 UK Hospitals

Introduction: It has been suggested that doctors in their first year of post-graduate training make a disproportionate number of prescribing errors.

Obkective: This study aimed to compare the prevalence of prescribing errors made by first-year post-graduate doctors with that of errors by senior doctors and non-medical prescribers and to investigate the predictors of potentially serious prescribing errors.

Methods: Pharmacists in 20 hospitals over 7 prospectively selected days collected data on the number of medication orders checked, the grade of prescriber and details of any prescribing errors. Logistic regression models (adjusted for clustering by hospital) identified factors predicting the likelihood of prescribing erroneously and the severity of prescribing errors.

Results: Pharmacists reviewed 26,019 patients and 124,260 medication orders; 11,235 prescribing errors were detected in 10,986 orders. The mean error rate was 8.8 % (95 % confidence interval [CI] 8.6-9.1) errors per 100 medication orders. Rates of errors for all doctors in training were significantly higher than rates for medical consultants. Doctors who were 1 year (odds ratio [OR] 2.13; 95 % CI 1.80-2.52) or 2 years in training (OR 2.23; 95 % CI 1.89-2.65) were more than twice as likely to prescribe erroneously. Prescribing errors were 70 % (OR 1.70; 95 % CI 1.61-1.80) more likely to occur at the time of hospital admission than when medication orders were issued during the hospital stay. No significant differences in severity of error were observed between grades of prescriber. Potentially serious errors were more likely to be associated with prescriptions for parenteral administration, especially for cardiovascular or endocrine disorders.

Conclusions: The problem of prescribing errors in hospitals is substantial and not solely a problem of the most junior medical prescribers, particularly for those errors most likely to cause significant patient harm. Interventions are needed to target these high-risk errors by all grades of staff and hence improve patient safety.

Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial

BACKGROUND: Acute promyelocytic leukaemia is a chemotherapy-sensitive subgroup of acute myeloid leukaemia characterised by the presence of the PML-RARA fusion transcript. The present standard of care, chemotherapy and all-trans retinoic acid (ATRA), results in a high proportion of patients being cured. In this study, we compare a chemotherapy-free ATRA and arsenic trioxide treatment regimen with the standard chemotherapy-based regimen (ATRA and idarubicin) in both high-risk and low-risk patients with acute promyelocytic leukaemia.

METHODS: In the randomised, controlled, multicentre, AML17 trial, eligible patients (aged ≥16 years) with acute promyelocytic leukaemia, confirmed by the presence of the PML-RARA transcript and without significant cardiac or pulmonary comorbidities or active malignancy, and who were not pregnant or breastfeeding, were enrolled from 81 UK hospitals and randomised 1:1 to receive treatment with ATRA and arsenic trioxide or ATRA and idarubicin. ATRA was given to participants in both groups in a daily divided oral dose of 45 mg/m(2) until remission, or until day 60, and then in a 2 weeks on-2 weeks off schedule. In the ATRA and idarubicin group, idarubicin was given intravenously at 12 mg/m(2) on days 2, 4, 6, and 8 of course 1, and then at 5 mg/m(2) on days 1-4 of course 2; mitoxantrone at 10 mg/m(2) on days 1-4 of course 3, and idarubicin at 12 mg/m(2) on day 1 of the final (fourth) course. In the ATRA and arsenic trioxide group, arsenic trioxide was given intravenously at 0·3 mg/kg on days 1-5 of each course, and at 0·25 mg/kg twice weekly in weeks 2-8 of course 1 and weeks 2-4 of courses 2-5. High-risk patients (those presenting with a white blood cell count >10 × 10(9) cells per L) could receive an initial dose of the immunoconjugate gemtuzumab ozogamicin (6 mg/m(2) intravenously). Neither maintenance treatment nor CNS prophylaxis was given to patients in either group. All patients were monitored by real-time quantitative PCR. Allocation was by central computer minimisation, stratified by age, performance status, and de-novo versus secondary disease. The primary endpoint was quality of life on the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 global health status. All analyses are by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN55675535.

FINDINGS: Between May 8, 2009, and Oct 3, 2013, 235 patients were enrolled and randomly assigned to ATRA and idarubicin (n=119) or ATRA and arsenic trioxide (n=116). Participants had a median age of 47 years (range 16-77; IQR 33-58) and included 57 high-risk patients. Quality of life did not differ significantly between the treatment groups (EORTC QLQ-C30 global functioning effect size 2·17 [95% CI -2·79 to 7·12; p=0·39]). Overall, 57 patients in the ATRA and idarubicin group and 40 patients in the ATRA and arsenic trioxide group reported grade 3-4 toxicities. After course 1 of treatment, grade 3-4 alopecia was reported in 23 (23%) of 98 patients in the ATRA and idarubicin group versus 5 (5%) of 95 in the ATRA and arsenic trioxide group, raised liver alanine transaminase in 11 (10%) of 108 versus 27 (25%) of 109, oral toxicity in 22 (19%) of 115 versus one (1%) of 109. After course 2 of treatment, grade 3-4 alopecia was reported in 25 (28%) of 89 patients in the ATRA and idarubicin group versus 2 (3%) of 77 in the ATRA and arsenic trioxide group; no other toxicities reached the 10% level. Patients in the ATRA and arsenic trioxide group had significantly less requirement for most aspects of supportive care than did those in the ATRA and idarubicin group.

INTERPRETATION: ATRA and arsenic trioxide is a feasible treatment in low-risk and high-risk patients with acute promyelocytic leukaemia, with a high cure rate and less relapse than, and survival not different to, ATRA and idarubicin, with a low incidence of liver toxicity. However, no improvement in quality of life was seen.

Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity.

Risk-aware Planning in BDI Agents

The ability of an autonomous agent to select rational actions is vital in enabling it to achieve its goals. To do so effectively in a high-stakes setting, the agent must be capable of considering the risk and potential reward of both immediate and future actions. In this paper we provide a novel method for calculating risk alongside utility in online planning algorithms. We integrate such a risk-aware planner with a BDI agent, allowing us to build agents that can set their risk aversion levels dynamically based on their changing beliefs about the environment. To guide the design of a risk-aware agent we propose a number of principles which such an agent should adhere to and show how our proposed framework satisfies these principles. Finally, we evaluate our approach and demonstrate that a dynamically risk-averse agent is capable of achieving a higher success rate than an agent that ignores risk, while obtaining a higher utility than an agent with a static risk attitude.

Increase in microbial contamination risk with compression of the lid margin in eyes having cataract surgery

Purpose: To assess the bacterial contamination risk in cataract surgery associated with mechanical compression of the lid margin immediately after sterilization of the ocular surface.

Setting: Department of Cataract, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.

Design: Prospective randomized controlled double-masked trial.

Methods: Patients with age-related cataract were randomly assigned to 1 of 2 groups. In Group A (153 eyes), the lid margin was compressed and scrubbed for 360 degrees 5 times with a dry sterile cotton-tipped applicator immediately after ocular sterilization and before povidone-iodine irrigation of the conjunctival sac. Group B (153 eyes) had identical sterilization but no lid scrubbing. Samples from the lid margin, liquid in the collecting bag, and aqueous humor were collected for bacterial culture. Primary outcome measures included the rate of positive bacterial culture for the above samples. The species of bacteria isolated were recorded.

Results: Group A and Group B each comprised 153 eyes. The positive rate of lid margin cultures was 54.24%. The positive rate of cultures for liquid in the collecting bag was significantly higher in Group A (23.53%) than in Group B (9.80%) (P=.001).The bacterial species cultured from the collecting bag in Group B were the same as those from the lid margin in Group A. The positive culture rate of aqueous humor in both groups was 0%.

Conclusion: Mechanical compression of the lid margin immediately before and during cataract surgery increased the risk for bacterial contamination of the surgical field, perhaps due to secretions from the lid margin glands.

Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned.