Functional annotation signatures of disease susceptibility loci improve SNP association analysis.

BACKGROUND: Genetic association studies are conducted to discover genetic loci that contribute to an inherited trait, identify the variants behind these associations and ascertain their functional role in determining the phenotype. To date, functional annotations of the genetic variants have rarely played more than an indirect role in assessing evidence for association. Here, we demonstrate how these data can be systematically integrated into an association study's analysis plan. RESULTS: We developed a Bayesian statistical model for the prior probability of phenotype-genotype association that incorporates data from past association studies and publicly available functional annotation data regarding the susceptibility variants under study. The model takes the form of a binary regression of association status on a set of annotation variables whose coefficients were estimated through an analysis of associated SNPs in the GWAS Catalog (GC). The functional predictors examined included measures that have been demonstrated to correlate with the association status of SNPs in the GC and some whose utility in this regard is speculative: summaries of the UCSC Human Genome Browser ENCODE super-track data, dbSNP function class, sequence conservation summaries, proximity to genomic variants in the Database of Genomic Variants and known regulatory elements in the Open Regulatory Annotation database, PolyPhen-2 probabilities and RegulomeDB categories. Because we expected that only a fraction of the annotations would contribute to predicting association, we employed a penalized likelihood method to reduce the impact of non-informative predictors and evaluated the model's ability to predict GC SNPs not used to construct the model. We show that the functional data alone are predictive of a SNP's presence in the GC. Further, using data from a genome-wide study of ovarian cancer, we demonstrate that their use as prior data when testing for association is practical at the genome-wide scale and improves power to detect associations. CONCLUSIONS: We show how diverse functional annotations can be efficiently combined to create 'functional signatures' that predict the a priori odds of a variant's association to a trait and how these signatures can be integrated into a standard genome-wide-scale association analysis, resulting in improved power to detect truly associated variants.

The Burden of Burnout: An Assessment of Burnout Among Internal Medicine Residents After the 2011 Duty Hour Changes.

This study sought to determine burnout prevalence and factors associated with burnout in internal medicine residents after introduction of the 2011 ACGME duty hour rules. Burnout was evaluated using an anonymized, abbreviated version of the Maslach Burnout Inventory. Surveys were collected biweekly for 48 weeks during the 2013-2014 academic year. Burnout severity was compared across subgroups and time. A score of 3 or higher signified burnout. Overall, 944 of 3936 (24%) surveys were completed. The mean burnout score across all surveys was 2.8. Categorical residents had higher burnout severity than noncategorical residents (2.9 vs 2.7, P = .005). Postgraduate year 2 residents had the highest burnout severity by year (3.1, P < .001). Residents on inpatient rotations had higher burnout severity than residents on outpatient or consultation rotations (3.1 vs 2.2 vs 2.2, P < .001). Night float rotations had the highest severity (3.8). Burnout remains a significant problem even with recent duty hour modifications.

The Excess Burden of Cytomegalovirus in African American Communities: A Geospatial Analysis.

Background.  Cytomegalovirus (CMV) is a common cause of birth defects and hearing loss in infants and opportunistic infections in the immunocompromised. Previous studies have found higher CMV seroprevalence rates among minorities and among persons with lower socioeconomic status. No studies have investigated the geographic distribution of CMV and its relationship to age, race, and poverty in the community. Methods.  We identified patients from 6 North Carolina counties who were tested in the Duke University Health System for CMV immunoglobulin G. We performed spatial statistical analyses to analyze the distributions of seropositive and seronegative individuals. Results.  Of 1884 subjects, 90% were either white or African American. Cytomegalovirus seropositivity was significantly more common among African Americans (73% vs 42%; odds ratio, 3.31; 95% confidence interval, 2.7-4.1), and this disparity persisted across the life span. We identified clusters of high and low CMV odds, both of which were largely explained by race. Clusters of high CMV odds were found in communities with high proportions of African Americans. Conclusions.  Cytomegalovirus seropositivity is geographically clustered, and its distribution is strongly determined by a community's racial composition. African American communities have high prevalence rates of CMV infection, and there may be a disparate burden of CMV-associated morbidity in these communities.

How common are common mental disorders? Evidence that lifetime prevalence rates are doubled by prospective versus retrospective ascertainment.

BACKGROUND: Most information about the lifetime prevalence of mental disorders comes from retrospective surveys, but how much these surveys have undercounted due to recall failure is unknown. We compared results from a prospective study with those from retrospective studies. METHOD: The representative 1972-1973 Dunedin New Zealand birth cohort (n=1037) was followed to age 32 years with 96% retention, and compared to the national New Zealand Mental Health Survey (NZMHS) and two US National Comorbidity Surveys (NCS and NCS-R). Measures were research diagnoses of anxiety, depression, alcohol dependence and cannabis dependence from ages 18 to 32 years. RESULTS: The prevalence of lifetime disorder to age 32 was approximately doubled in prospective as compared to retrospective data for all four disorder types. Moreover, across disorders, prospective measurement yielded a mean past-year-to-lifetime ratio of 38% whereas retrospective measurement yielded higher mean past-year-to-lifetime ratios of 57% (NZMHS, NCS-R) and 65% (NCS). CONCLUSIONS: Prospective longitudinal studies complement retrospective surveys by providing unique information about lifetime prevalence. The experience of at least one episode of DSM-defined disorder during a lifetime may be far more common in the population than previously thought. Research should ask what this means for etiological theory, construct validity of the DSM approach, public perception of stigma, estimates of the burden of disease and public health policy.

Prayer and Depression: Women in Rural Pakistan

Background: Mental health, specifically depression, is a burden of disease in Pakistan. Religion and depression have not been studied in Pakistan currently, specially within a subset of a rural population. Methods: A secondary-data analysis was conducted using logistic regression for a non-parametrically distributed data set. The setting was in rural Pakistan, near Rawalpindi, and the sample size data was collected from the SHARE (South Asian Hub for Advocacy, Research, and Education). The measures used were the phq9 scaled for depression, prayer number, mother’s education, mother’s age, and if the mothers work. Results: This study demonstrated that there was no association between prayer and depression in this cohort. The mean prayer number between depressed and non-depressed women was 1.22 and 1.42, respectively, and a Wilcoxan rank sum test indicated that this was not significant. Conclusions: The primary finding indicates that increased frequency of prayer is not associated with a decreased rate of depression. This may be due to prayer number not being a significant enough measure. The implications of these findings stress the need for more depression intervention in rural Pakistan.

Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001-2006: overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database.

BACKGROUND: The incidence and epidemiology of invasive fungal infections (IFIs), a leading cause of death among hematopoeitic stem cell transplant (HSCT) recipients, are derived mainly from single-institution retrospective studies. METHODS: The Transplant Associated Infections Surveillance Network, a network of 23 US transplant centers, prospectively enrolled HSCT recipients with proven and probable IFIs occurring between March 2001 and March 2006. We collected denominator data on all HSCTs preformed at each site and clinical, diagnostic, and outcome information for each IFI case. To estimate trends in IFI, we calculated the 12-month cumulative incidence among 9 sequential subcohorts. RESULTS: We identified 983 IFIs among 875 HSCT recipients. The median age of the patients was 49 years; 60% were male. Invasive aspergillosis (43%), invasive candidiasis (28%), and zygomycosis (8%) were the most common IFIs. Fifty-nine percent and 61% of IFIs were recognized within 60 days of neutropenia and graft-versus-host disease, respectively. Median onset of candidiasis and aspergillosis after HSCT was 61 days and 99 days, respectively. Within a cohort of 16,200 HSCT recipients who received their first transplants between March 2001 and September 2005 and were followed up through March 2006, we identified 718 IFIs in 639 persons. Twelve-month cumulative incidences, based on the first IFI, were 7.7 cases per 100 transplants for matched unrelated allogeneic, 8.1 cases per 100 transplants for mismatched-related allogeneic, 5.8 cases per 100 transplants for matched-related allogeneic, and 1.2 cases per 100 transplants for autologous HSCT. CONCLUSIONS: In this national prospective surveillance study of IFIs in HSCT recipients, the cumulative incidence was highest for aspergillosis, followed by candidiasis. Understanding the epidemiologic trends and burden of IFIs may lead to improved management strategies and study design.

Genome-wide scan of copy number variation in late-onset Alzheimer's disease.

Alzheimer's disease is a complex and progressive neurodegenerative disease leading to loss of memory, cognitive impairment, and ultimately death. To date, six large-scale genome-wide association studies have been conducted to identify SNPs that influence disease predisposition. These studies have confirmed the well-known APOE epsilon4 risk allele, identified a novel variant that influences disease risk within the APOE epsilon4 population, found a SNP that modifies the age of disease onset, as well as reported the first sex-linked susceptibility variant. Here we report a genome-wide scan of Alzheimer's disease in a set of 331 cases and 368 controls, extending analyses for the first time to include assessments of copy number variation. In this analysis, no new SNPs show genome-wide significance. We also screened for effects of copy number variation, and while nothing was significant, a duplication in CHRNA7 appears interesting enough to warrant further investigation.

A dimensionless number for understanding the evolutionary dynamics of antigenically variable RNA viruses.

Antigenically variable RNA viruses are significant contributors to the burden of infectious disease worldwide. One reason for their ubiquity is their ability to escape herd immunity through rapid antigenic evolution and thereby to reinfect previously infected hosts. However, the ways in which these viruses evolve antigenically are highly diverse. Some have only limited diversity in the long-run, with every emergence of a new antigenic variant coupled with a replacement of the older variant. Other viruses rapidly accumulate antigenic diversity over time. Others still exhibit dynamics that can be considered evolutionary intermediates between these two extremes. Here, we present a theoretical framework that aims to understand these differences in evolutionary patterns by considering a virus's epidemiological dynamics in a given host population. Our framework, based on a dimensionless number, probabilistically anticipates patterns of viral antigenic diversification and thereby quantifies a virus's evolutionary potential. It is therefore similar in spirit to the basic reproduction number, the well-known dimensionless number which quantifies a pathogen's reproductive potential. We further outline how our theoretical framework can be applied to empirical viral systems, using influenza A/H3N2 as a case study. We end with predictions of our framework and work that remains to be done to further integrate viral evolutionary dynamics with disease ecology.

Live Imaging of Host-Parasite Interactions in a Zebrafish Infection Model Reveals Cryptococcal Determinants of Virulence and Central Nervous System Invasion.

UNLABELLED: The human fungal pathogen Cryptococcus neoformans is capable of infecting a broad range of hosts, from invertebrates like amoebas and nematodes to standard vertebrate models such as mice and rabbits. Here we have taken advantage of a zebrafish model to investigate host-pathogen interactions of Cryptococcus with the zebrafish innate immune system, which shares a highly conserved framework with that of mammals. Through live-imaging observations and genetic knockdown, we establish that macrophages are the primary immune cells responsible for responding to and containing acute cryptococcal infections. By interrogating survival and cryptococcal burden following infection with a panel of Cryptococcus mutants, we find that virulence factors initially identified as important in causing disease in mice are also necessary for pathogenesis in zebrafish larvae. Live imaging of the cranial blood vessels of infected larvae reveals that C. neoformans is able to penetrate the zebrafish brain following intravenous infection. By studying a C. neoformans FNX1 gene mutant, we find that blood-brain barrier invasion is dependent on a known cryptococcal invasion-promoting pathway previously identified in a murine model of central nervous system invasion. The zebrafish-C. neoformans platform provides a visually and genetically accessible vertebrate model system for cryptococcal pathogenesis with many of the advantages of small invertebrates. This model is well suited for higher-throughput screening of mutants, mechanistic dissection of cryptococcal pathogenesis in live animals, and use in the evaluation of therapeutic agents. IMPORTANCE: Cryptococcus neoformans is an important opportunistic pathogen that is estimated to be responsible for more than 600,000 deaths worldwide annually. Existing mammalian models of cryptococcal pathogenesis are costly, and the analysis of important pathogenic processes such as meningitis is laborious and remains a challenge to visualize. Conversely, although invertebrate models of cryptococcal infection allow high-throughput assays, they fail to replicate the anatomical complexity found in vertebrates and, specifically, cryptococcal stages of disease. Here we have utilized larval zebrafish as a platform that overcomes many of these limitations. We demonstrate that the pathogenesis of C. neoformans infection in zebrafish involves factors identical to those in mammalian and invertebrate infections. We then utilize the live-imaging capacity of zebrafish larvae to follow the progression of cryptococcal infection in real time and establish a relevant model of the critical central nervous system infection phase of disease in a nonmammalian model.

Mobile Clinics & Bundled Healthcare: An Exploration of Patient Perceptions of the SughaVazhvu Approach to Chronic Care Management

As the burden of non-communicable diseases increases worldwide, it is imperative that health systems adopt delivery approaches that will enable them to provide accessible, high-quality, and low-cost care to patients that need consistent management of their lifelong conditions. This is especially true in low- and middle-income country settings, such as India, where the disease burden is high and the health sector resources to address it are limited. The subscription-based, managed care model that SughaVazhvu Healthcare—a non-profit social enterprise operating in rural Thanjavur, Tamil Nadu—has deployed demonstrates potential for ensuring continuity of care among chronic care patients in resource-strained areas. However, its effectiveness and sustainability will depend on its ability to positively impact patient health status and patient satisfaction with the care management they are receiving. Therefore, this study is not only a program appraisal to aid operational quality improvement of the SughaVazhvu Healthcare model, but also an attempt to identify the factors that affect patient satisfaction among individuals with chronic conditions actively availing services.

Understanding Antenatal Genetics Services in Sri Lanka: Current Landscape of Screening and Diagnostic Services and Contextual Factors Influencing Their Availability and Uptake

Background: Too little information is available on Sri Lanka’s current capacity to provide community genetic services—antenatal genetic services in particular—to understand whether building that capacity could further improve and reduce disparity in maternal and child health. This qualitative research project seeks to gather information on congenital disorders, routine antenatal care, and the current state of antenatal screening testing services within that routine antenatal to assess the feasibility of and the need for scaling up antenatal genetics services in Sri Lanka. Methods: Nineteen key informant (KI) interviews were conducted with stakeholders in antenatal care and genetic services. Seven focus group discussions were held with a total of 56 Public Health Midwives (PHMs), the health workers responsible for antenatal care at the field level. Transcripts for all interviews and FGDs were analyzed for key themes, and themes were categorized to address the specific aims of the project. Results: Antenatal genetic services play a minor role in antenatal care, with screening and diagnostic procedures available in the private sector and paid for out-of-pocket. KIs and PHMs expect that demand for antenatal genetic services will increase as patients’ purchasing power and knowledge grow but note that prohibitive abortion laws limit the ability of patients to act on test results. Genetic services compete for limited financial and human resources in the free public health system, and inadequate information on the prevalence of congenital disorders limits the ability to understand whether funding for services related to those disorders should be increased. A number of alternatives to scaling up antenatal genetic services within the free health system might be better suited to the Sri Lankan structural and social context. Conclusions: Scaling up antenatal genetic services within the public health system is not feasible in the current financial, legal, and human resource context. Yet current availability and utilization patterns contribute to regional and economic disparities, suggesting that stasis will not bring continued improvements in maternal and child health. More information on the burden of congenital disorders is necessary to fully understand if and how antenatal genetic service availability should be increased in Sri Lanka, but even before that information is gathered, examination of policies for patient referral, termination of pregnancy, and government support for individuals with genetic disease are steps that might bring extend improvements and reduce disparity in maternal and child health.

A Systematic Review of Race and Ethnicity in Hepatitis C Clinical Trial Enrollment.

The African American/Black population in the United States (US) is disproportionately affected by hepatitis C virus (HCV) and has lower response rates to current treatments. This analysis evaluates the participation of African American/Blacks in North American and European HCV clinical trials. The data source for this analysis was the PubMed database. Randomized controlled clinical trials (RCT) on HCV treatment with interferon 2a or 2b between January 2000 and December 2011 were reviewed. Inclusion criteria included English language and participants 18 years or older with chronic HCV. Exclusion criteria included non-randomized trials, case reports, cohort studies, ethnic specific studies, or studies not using interferon-alfa or PEG-interferon. Of the 588 trials identified, 314 (53.4%) fit inclusion criteria. The main outcome was the rate of African American/ Black participation in North American HCV clinical trials. A meta-analysis comparing the expected and observed rates was performed. Of the RCT's that met search criteria, 123 (39.2%) reported race. Clinical trials in North America were more likely to report racial data than European trials. Racial reporting increased over time. There was a statistically significant difference among the expected and observed participation of African Americans in HCV clinical trials in North America based on the prevalence of this disease within the population. The burden of HCV among African Americans in North America is not reflected in those clinical trials designed to treat HCV. Research on minority participation in clinical trials and how to increase minority participation in clinical trials is needed.