A Strategy For Identifying Putative Causes Of Gene Expression Variation In Human Cancer

There is often a need to predict the impact of alterations in one variable on another variable. This is especially the case in cancer research, where much effort has been made to carry out large-scale gene expression screening by microarray techniques. However, the causes of this variability from one cancer to another and from one gene to another often remain unknown. In this study we present a systematic procedure for finding genes whose expression is altered by an intrinsic or extrinsic explanatory phenomenon. The procedure has three stages: preprocessing, data integration and statistical analysis. We tested and verified the utility of this approach in a study, where expression and copy number of 13,824 genes were determined in 14 breast cancer samples. The expression of 270 genes could be explained by the variability of gene copy number. These genes may represent an important set of primary, genetically "damaged" genes that drive cancer progression

Intracerebral Hemorrhage among Blood Donors and Their Transfusion Recipients

Importance: Recent reports have suggested that cerebral amyloid angiopathy, a common cause of multiple spontaneous intracerebral hemorrhages (ICHs), may be transmissible through parenteral injection of contaminated cadaveric pituitary hormone in humans. Objective: To determine whether spontaneous ICH in blood donors after blood donation is associated with development of spontaneous ICH in transfusion recipients. Design, Setting, and Participants: Exploratory retrospective cohort study using nationwide blood bank and health register data from Sweden (main cohort) and Denmark (validation cohort) and including all 1089370 patients aged 5 to 80 years recorded to have received a red blood cell transfusion from January 1, 1970 (Sweden), or January 1, 1980 (Denmark), until December 31, 2017. Exposures: Receipt of red blood cell transfusions from blood donors who subsequently developed (1) a single spontaneous ICH, (2) multiple spontaneous ICHs, or (3) no spontaneous ICH. Main Outcomes and Measures: Spontaneous ICH in transfusion recipients; ischemic stroke was a negative control outcome. Results: A total of 759858 patients from Sweden (median age, 65 [IQR, 48-73] years; 59% female) and 329512 from Denmark (median age, 64 [IQR, 50-73] years; 58% female) were included, with a median follow-up of 5.8 (IQR, 1.4-12.5) years and 6.1 (IQR, 1.5-11.6) years, respectively. Patients who underwent transfusion with red blood cell units from donors who developed multiple spontaneous ICHs had a significantly higher risk of a single spontaneous ICH themselves, compared with patients receiving transfusions from donors who did not develop spontaneous ICH, in both the Swedish cohort (unadjusted incidence rate [IR], 3.16 vs 1.12 per 1000 person-years; adjusted hazard ratio [HR], 2.73; 95% CI, 1.72-4.35; P <.001) and the Danish cohort (unadjusted IR, 2.82 vs 1.09 per 1000 person-years; adjusted HR, 2.32; 95% CI, 1.04-5.19; P =.04). No significant difference was found for patients receiving transfusions from donors who developed a single spontaneous ICH in the Swedish cohort (unadjusted IR, 1.35 vs 1.12 per 1000 person-years; adjusted HR, 1.06; 95% CI, 0.84-1.36; P =.62) nor the Danish cohort (unadjusted IR, 1.36 vs 1.09 per 1000 person-years; adjusted HR, 1.06; 95% CI, 0.70-1.60; P =.73), nor for ischemic stroke as a negative control outcome. Conclusions and Relevance: In an exploratory analysis of patients who received red blood cell transfusions, patients who underwent transfusion with red blood cells from donors who later developed multiple spontaneous ICHs were at significantly increased risk of spontaneous ICH themselves. This may suggest a transfusion-transmissible agent associated with some types of spontaneous ICH, although the findings may be susceptible to selection bias and residual confounding, and further research is needed to investigate if transfusion transmission of cerebral amyloid angiopathy might explain this association.

Topological Field Theories and Geometry of Batalin-Vilkovisky Algebras

The algebraic and geometric structures of deformations are analyzed concerning topological field theories of Schwarz type by means of the Batalin-Vilkovisky formalism. Deformations of the Chern-Simons-BF theory in three dimensions induces the Courant algebroid structure on the target space as a sigma model. Deformations of BF theories in $n$ dimensions are also analyzed. Two dimensional deformed BF theory induces the Poisson structure and three dimensional deformed BF theory induces the Courant algebroid structure on the target space as a sigma model. The deformations of BF theories in $n$ dimensions induce the structures of Batalin-Vilkovisky algebras on the target space.Comment: 25 page

Health services research in the public healthcare system in Hong Kong: An analysis of over 1 million antihypertensive prescriptions between 2004-2007 as an example of the potential and pitfalls of using routinely collected electronic patient data

&lt;b&gt;Objectives&lt;/b&gt; Increasing use is being made of routinely collected electronic patient data in health services research. The aim of the present study was to evaluate the potential usefulness of a comprehensive database used routinely in the public healthcare system in Hong Kong, using antihypertensive drug prescriptions in primary care as an example.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methods&lt;/b&gt; Data on antihypertensive drug prescriptions were retrieved from the electronic Clinical Management System (e-CMS) of all primary care clinics run by the Health Authority (HA) in the New Territory East (NTE) cluster of Hong Kong between January 2004 and June 2007. Information was also retrieved on patients’ demographic and socioeconomic characteristics, visit type (new or follow-up), and relevant diseases (International Classification of Primary Care, ICPC codes). &lt;p&gt;&lt;/p&gt; &lt;b&gt;Results&lt;/b&gt; 1,096,282 visit episodes were accessed, representing 93,450 patients. Patients’ demographic and socio-economic details were recorded in all cases. Prescription details for anti-hypertensive drugs were missing in only 18 patients (0.02%). However, ICPC-code was missing for 36,409 patients (39%). Significant independent predictors of whether disease codes were applied included patient age &gt; 70 years (OR 2.18), female gender (OR 1.20), district of residence (range of ORs in more rural districts; 0.32-0.41), type of clinic (OR in Family Medicine Specialist Clinics; 1.45) and type of visit (OR follow-up visit; 2.39). &lt;p&gt;&lt;/p&gt; In the 57,041 patients with an ICPC-code, uncomplicated hypertension (ICPC K86) was recorded in 45,859 patients (82.1%). The characteristics of these patients were very similar to those of the non-coded group, suggesting that most non-coded patients on antihypertensive drugs are likely to have uncomplicated hypertension. &lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusion&lt;/b&gt; The e-CMS database of the HA in Hong Kong varies in quality in terms of recorded information. Potential future health services research using demographic and prescription information is highly feasible but for disease-specific research dependant on ICPC codes some caution is warranted. In the case of uncomplicated hypertension, future research on pharmaco-epidemiology (such as prescription patterns) and clinical issues (such as side-effects of medications on metabolic parameters) seems feasible given the large size of the data set and the comparability of coded and non-coded patients

Estimating heritability and genetic correlations from large health datasets in the absence of genetic data

Typically, estimating genetic parameters, such as disease heritability and between-disease genetic correlations, demands large datasets containing all relevant phenotypic measures and detailed knowledge of family relationships or, alternatively, genotypic and phenotypic data for numerous unrelated individuals. Here, we suggest an alternative, efficient estimation approach through the construction of two disease metrics from large health datasets: temporal disease prevalence curves and low-dimensional disease embeddings. We present eleven thousand heritability estimates corresponding to five study types: twins, traditional family studies, health records-based family studies, single nucleotide polymorphisms, and polygenic risk scores. We also compute over six hundred thousand estimates of genetic, environmental and phenotypic correlations. Furthermore, we find that: (1) disease curve shapes cluster into five general patterns; (2) early-onset diseases tend to have lower prevalence than late-onset diseases (Spearmans rho = 0.32, p amp;lt; 10(-16)); and (3) the disease onset age and heritability are negatively correlated (rho = -0.46, p amp;lt; 10(-16)).Funding Agencies|DARPA Big Mechanism program under ARO [W911NF1410333]; National Institutes of HealthUnited States Department of Health &amp; Human ServicesNational Institutes of Health (NIH) - USA [R01HL122712, 1P50MH094267, U01HL108634-01]; King Abdullah University of Science and Technology (KAUST)King Abdullah University of Science &amp; Technology [FCC/1/1976-18-01, FCC/1/1976-23-01, FCC/1/1976-25-01, FCC/1/1976-26-01, FCS/1/4102-02-01]</p

Estimating heritability and genetic correlations from large health datasets in the absence of genetic data.

Typically, estimating genetic parameters, such as disease heritability and between-disease genetic correlations, demands large datasets containing all relevant phenotypic measures and detailed knowledge of family relationships or, alternatively, genotypic and phenotypic data for numerous unrelated individuals. Here, we suggest an alternative, efficient estimation approach through the construction of two disease metrics from large health datasets: temporal disease prevalence curves and low-dimensional disease embeddings. We present eleven thousand heritability estimates corresponding to five study types: twins, traditional family studies, health records-based family studies, single nucleotide polymorphisms, and polygenic risk scores. We also compute over six hundred thousand estimates of genetic, environmental and phenotypic correlations. Furthermore, we find that: (1) disease curve shapes cluster into five general patterns; (2) early-onset diseases tend to have lower prevalence than late-onset diseases (Spearman\u27s ρ = 0.32, p \u3c 1

Association between statin use after diagnosis of esophageal cancer and survival: a population-based cohort study

Background & Aims: Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors), commonly prescribed to prevent cardiovascular disease, promote apoptosis and limit proliferation of esophageal cancer cell lines. We investigated whether statin use following diagnosis of esophageal cancer is associated with reduced esophageal cancer-specific and all-cause mortality.  Methods: We identified a cohort of 4445 men and women in the United Kingdom diagnosed with esophageal cancer from January 2000 through November 2009 using the General Practice Research Database. The National Cancer Registry and Office of National Statistics datasets respectively established the histologic subtype and cancer-specific mortality. Cox proportional hazard regression analysis with time-dependent exposures estimated the association between statin use after diagnosis and esophageal cancer-specific and all-cause mortality.  Results: The median survival time of the entire cohort was 9.2 months (inter-quartile range [IQR], 3.7–23.2 months). Among subjects who used statins after diagnosis of esophageal cancer, the median survival time was 14.9 months (IQR, 7.1–52.3) compared to 8.1 months for non-users (IQR, 3.3–20). In the entire cohort, statin use after diagnosis was associated with a decreased risk of esophageal cancer-specific mortality (adjusted hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.44–0.86) and all-cause mortality (HR, 0.67; 95% CI, 0.58–0.77). In patients with esophageal adenocarcinoma, statin use after diagnosis was associated with decreased risk of esophageal cancer-specific mortality (HR, 0.61; 95% CI 0.38–0.96) and all-cause mortality (HR, 0.63; 95% 0.43–0.92). This effect was not observed in patients with esophageal squamous cell carcinoma. There was no evidence for effect modification of these associations with statin use before cancer diagnosis.  Conclusions: In a large population-based cohort, statin use after diagnosis of esophageal adenocarcinoma, but not esophageal squamous cell carcinoma, was associated with reduced esophageal cancer-specific and all-cause mortality

A clinical and EEG scoring system that predicts early cortical response (N20) to somatosensory evoked potentials and outcome after cardiac arrest

<p>Abstract</p> <p>Background</p> <p>Anoxic coma following cardiac arrest is a common problem with ethical, social, and legal consequences. Except for unfavorable somatosensory-evoked potentials (SSEP) results, predictors of unfavorable outcome with a 100% specificity and a high sensitivity are lacking. The aim of the current research was to construct a clinical and EEG scoring system that predicts early cortical response (N20) to somatosensory evoked potentials and 6-months outcome in comatose patients after cardiac arrest.</p> <p>Methods</p> <p>We retrospectively reviewed the records of all consecutive patients who suffered cardiac arrest outside our hospital and were subsequently admitted to our facility from November 2002 to July 2006. We scored each case based on early clinical and EEG factors associated with unfavorable SSEPs, and we assessed the ability of this score to predict SSEP results and outcome.</p> <p>Results</p> <p>Sixty-six patients qualified for inclusion in the cohort. Among them, 34 (52%) had unfavorable SSEP results. At day three, factors independently associated with unfavorable SSEPs were: absence of corneal (14 points) and pupillary (21 points) reflexes, myoclonus (25 points), extensor or absent motor response to painful stimulation (28 points), and malignant EEG (11 points). A score >40 points had a sensitivity of 85%, a specificity of 84%, and a positive predictive value (PPV) of 85% to predict unfavorable SSEP results. A score >88 points had a PPV of 100%, but a sensitivity of 18%. Overall, this score had an area under ROC curves of 0.919. In addition, at day three, a score > 69 points had a PPV of 100% with a sensitivity of 32% to predict death or vegetative state.</p> <p>Conclusion</p> <p>A scoring system based on a combination of clinical and EEG findings can predict the absence of early cortical response to SSEPs. In settings without access to SSEPs, this score may help decision-making in a subset of comatose survivors after a cardiac arrest.</p

Live lecture versus video podcast in undergraduate medical education: A randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Information technology is finding an increasing role in the training of medical students. We compared information recall and student experience and preference after live lectures and video podcasts in undergraduate medical education.</p> <p>Methods</p> <p>We performed a crossover randomised controlled trial. 100 students were randomised to live lecture or video podcast for one clinical topic. Live lectures were given by the same instructor as the narrator of the video podcasts. The video podcasts comprised Powerpoint™ slides narrated using the same script as the lecture. They were then switched to the other group for a second clinical topic. Knowledge was assessed using multiple choice questions and qualitative information was collected using a questionnaire.</p> <p>Results</p> <p>No significant difference was found on multiple choice questioning immediately after the session. The subjects enjoyed the convenience of the video podcast and the ability to stop, review and repeat it, but found it less engaging as a teaching method. They expressed a clear preference for the live lecture format.</p> <p>Conclusions</p> <p>We suggest that video podcasts are not ready to replace traditional teaching methods, but may have an important role in reinforcing learning and aiding revision.</p