Estimating cell type composition using isoform expression one gene at a time.

Human tissue samples are often mixtures of heterogeneous cell types, which can confound the analyses of gene expression data derived from such tissues. The cell type composition of a tissue sample may itself be of interest and is needed for proper analysis of differential gene expression. A variety of computational methods have been developed to estimate cell type proportions using gene-level expression data. However, RNA isoforms can also be differentially expressed across cell types, and isoform-level expression could be equally or more informative for determining cell type origin than gene-level expression. We propose a new computational method, IsoDeconvMM, which estimates cell type fractions using isoform-level gene expression data. A novel and useful feature of IsoDeconvMM is that it can estimate cell type proportions using only a single gene, though in practice we recommend aggregating estimates of a few dozen genes to obtain more accurate results. We demonstrate the performance of IsoDeconvMM using a unique data set with cell type-specific RNA-seq data across more than 135 individuals. This data set allows us to evaluate different methods given the biological variation of cell type-specific gene expression data across individuals. We further complement this analysis with additional simulations.

ICeD-T Provides Accurate Estimates of Immune Cell Abundance in Tumor Samples by Allowing for Aberrant Gene Expression Patterns.

Immunotherapies have attracted lots of research interests recently. The need to understand the underlying mechanisms of immunotherapies and to develop precision immunotherapy regimens has spurred great interest in characterizing immune cell composition within the tumor microenvironment. Several methods have been developed to estimate immune cell composition using gene expression data from bulk tumor samples. However, these methods are not flexible enough to handle aberrant patterns of gene expression data, e.g., inconsistent cell type-specific gene expression between purified reference samples and tumor samples. We propose a novel statistical method for expression deconvolution called ICeD-T (Immune Cell Deconvolution in Tumor tissues). ICeD-T automatically identifies aberrant genes whose expression are inconsistent with the deconvolution model and down-weights their contributions to cell type abundance estimates. We evaluated the performance of ICeD-T versus existing methods in simulation studies and several real data analyses. ICeD-T displayed comparable or superior performance to these competing methods. Applying these methods to assess the relationship between immunotherapy response and immune cell composition, ICeD-T is able to identify significant associations that are missed by its competitors.

Mapping Tumor-Specific Expression QTLs in Impure Tumor Samples.

The study of gene expression quantitative trait loci (eQTL) is an effective approach to illuminate the functional roles of genetic variants. Computational methods have been developed for eQTL mapping using gene expression data from microarray or RNA-seq technology. Application of these methods for eQTL mapping in tumor tissues is problematic because tumor tissues are composed of both tumor and infiltrating normal cells (e.g. immune cells) and eQTL effects may vary between tumor and infiltrating normal cells. To address this challenge, we have developed a new method for eQTL mapping using RNA-seq data from tumor samples. Our method separately estimates the eQTL effects in tumor and infiltrating normal cells using both total expression and allele-specific expression (ASE). We demonstrate that our method controls type I error rate and has higher power than some alternative approaches. We applied our method to study RNA-seq data from The Cancer Genome Atlas and illustrated the similarities and differences of eQTL effects in tumor and normal cells.

A pilot study of eptifibatide for treatment of acute pain episodes in sickle cell disease.

INTRODUCTION: The contribution of platelet activation to the pathogenesis of sickle cell disease (SCD) remains uncertain. We evaluated the safety and efficacy of eptifibatide, a synthetic peptide inhibitor of the αIIbß3 receptor, in SCD patients during acute painful episodes. MATERIALS AND METHODS: In this single site, double-blind, placebo-controlled trial, eligible patients with SCD admitted for acute painful episodes were randomized to receive eptifibatide or placebo at a ratio of 2:1. RESULTS: Thirteen patients (SS - 10, Sß(0) - 2, SC - 1) were randomized to receive either eptifibatide (N=9; 6 females; median age - 25years) or placebo (N=4; 3 females; median age - 31years). In the intent-to-treat analysis, there were no major bleeding episodes in either the eptifibatide or placebo arms (point estimate of difference: 0.00, 95% CI; -0.604, 0.372). There was one minor bleeding episode in the eptifibatide arm (point estimate of difference for any bleeding: 0.11, 95% CI: -0.502, 0.494). There was no significant difference in the proportion of patients with thrombocytopenia between the treatment groups (point estimate of difference: 0.11, 95% CI: -0.587, 0.495). There were no differences in the median times to discharge, median times to crisis resolution or the median total opioid use. CONCLUSIONS: In this small study, eptifibatide appeared to be safe, but did not improve the times to crisis resolution or hospital discharge. Adequately powered studies are required to evaluate the safety and efficacy of eptifibatide in SCD. Clinicaltrials.gov Identifier: NCT00834899.

Improving the Quality and Capacity of Canada's Health Services: Primary Care Physician Perspectives.

OBJECTIVE: This study set out to identify the perspectives of family physicians (FP/GPs) on the quality and capacity of the services they provide and of the system in which they work, to assess their responsiveness to potential changes and to determine their suggestions for future directions to enhance primary care services. METHODS: Thematic results from prior focus groups with FP/GPs provided direction for a questionnaire sent to practitioners in the urban study area. Seventy-four questions, most using a five-point Likert scale, were grouped into 10 sections: physician issues (based on themes from the focus groups), access to specialist services, workload, scope of practice, primary care physician networks, interdisciplinary collaborative practice, complexities and challenges of family practice, future directions, comments and demographics. RESULTS: Five hundred and eighty-three FP/GPs were surveyed, and 300 responses (52%) were analyzed for frequencies and comparisons using SPSS. In addition to informative responses to the various survey sections noted above, specific physician suggestions for future directions to improve quality and capacity were identified. These included access to specialists/consultants, teamwork/collaborative practice, access to diagnostics, electronic records/technology, time and remuneration. CONCLUSIONS: The identified suggestions by FP/GPs to enhance the quality and capacity of health services contribute to a framework for policy development at national, provincial/territorial and regional levels and can be used as a reference point for the progress of primary care reform initiatives.

Socio-economic status and types of childhood injury in Alberta: a population based study.

BACKGROUND: Childhood injury is the leading cause of mortality, morbidity and permanent disability in children in the developed world. This research examines relationships between socio-economic status (SES), demographics, and types of childhood injury in the province of Alberta, Canada. METHODS: Secondary analysis was performed using administrative health care data provided by Alberta Health and Wellness on all children, aged 0 to 17 years, who had injuries treated by a physician, either in a physician's office, outpatient department, emergency room and/or as a hospital inpatient, between April 1st. 1995 to March 31st. 1996. Thirteen types of childhood injury were assessed with respect to age, gender and urban/rural location using ICD9 codes, and were related to SES as determined by an individual level SES indicator, the payment status of the Alberta provincial health insurance plan. The relationships between gender, SES, rural/urban status and injury type were determined using logistic regression. RESULTS: Twenty-four percent of Alberta children had an injury treated by physician during the one year period. Peak injury rates occurred about ages 2 and 13-17 years. All injury types except poisoning were more common in males. Injuries were more frequent in urban Alberta and in urban children with lower SES (receiving health care premium assistance). Among the four most common types of injury (78.6% of the total), superficial wounds and open wounds were more common among children with lower SES, while fractures and dislocations/sprains/strains were more common among children receiving no premium assistance. CONCLUSION: These results show that childhood injury in Alberta is a major health concern especially among males, children living in urban centres, and those living on welfare or have Treaty status. Most types of injury were more frequent in children of lower SES. Analysis of the three types of the healthcare premium subsidy allowed a more comprehensive picture of childhood injury with children whose families are on welfare and those of Treaty status presenting more frequently for an injury-related physician's consultation than other children. This report also demonstrates that administrative health care data can be usefully employed to describe injury patterns in children.

Virtual visiting seminar replaces verbatim seminar in Clinical Pastoral Education (CPE).

The article addresses the question of the value of the virtual visiting seminar compared to the verbatim seminar in a Clinical Pastoral Education (CPE) Unit. A Virtual Visit occurs when a volunteer allows a CPE student to engage them in a pastoral visit with the expressed purpose of providing feedback to the student. The effectiveness of the virtual visiting seminar was monitored by a Site Review Team, two independent expert witnesses, by students who have experienced both learning tools, and the Education Sub Committee of the Pastoral Care Advisory Committee. The results point to advantages of the virtual visiting seminar over the verbatim seminar.

Development and testing of a framework for assessing the effectiveness of health promotion.

OBJECTIVES: The purpose was to develop and test a framework for assessing the overall effectiveness of health promotion in one Canadian province. METHODS: The project relied on expert opinion and consensus. A multidisciplinary team developed a Project Description Framework and a Health Promotion Evaluation Framework. Two sets of inclusion criteria were developed for selecting projects to be assessed using the Framework. The sampling frame was all health promotion projects starting in Alberta in January 1993 or later for which a written program evaluation could be obtained. Of 180 project reports, 91 met the first set and 35 met the remaining inclusion criteria. Two research associates independently used the Project Description Framework. Three associates independently applied the inclusion criteria. Consensus was reached in all cases. Research team members used the Health Promotion Evaluation Framework to assess the 35 projects and to comment on its utility and any gaps identified. RESULTS: A framework for assessing the effectiveness of health promotion was developed and tested. CONCLUSION: This framework is a useful tool as evidenced by the review that was obtained and subsequent applications.

Internet users' prior psychological and social difficulties.

This study addressed the hypothesis that frequent Internet use produces social and psychological difficulties. An Internet-administered survey was given to a sample of Internet users. Comparisons were made between this sample and general population norms on a selection of social and psychological variables. Internet users showed a more detrimental mean rating on 11 of 13 of the variables (two measures of social contact were more positive among the user sample). However, for those variables for which time of onset was available (n = 7), the disorder had begun 5-22 years before Internet use. These findings are not in accord with the theory that Internet use causes disorder or social difficulty, and suggest the possibility that the Internet may provide a particular benefit for certain individuals who have already displayed these personal and social difficulties.

Developing a school asthma policy.

Schools are faced with the challenging mandate of addressing the learning needs of students while simultaneously managing a gamut of behavior and health problems. School health policies have been successfully used for many health-related issues. Although asthma is the most common chronic disease among children, schools receive only a small amount of support to manage asthma issues. This article describes our experiences in developing an asthma policy in schools. The problem of asthma in schools was assessed as part of a comprehensive community-based asthma intervention, and a plan was established to develop a school asthma policy. The goal of the policy was to facilitate a physical and social environment that enabled students with asthma to control optimally their condition, have a good quality of life, and learn effectively. Specific objectives included enhancing environmental control, educating staff, clarifying medication protocols, and responding appropriately to symptoms. Strategies in developing the policy included strengthening collaboration and networks among health, school, and community sectors; defining the role of the school and health sectors; designing the policy; refining the policy based on stakeholder feedback; and developing an evaluation plan.