RESUMO
RATIONALE: Variation in hospital mortality has been described for coronavirus disease 2019 (COVID-19), but the factors that explain these differences remain unclear. OBJECTIVE: Our objective was to utilize a large, nationally representative dataset of critically ill adults with COVID-19 to determine which factors explain mortality variability. METHODS: In this multicenter cohort study, we examined adults hospitalized in intensive care units with COVID-19 at 70 United States hospitals between March and June 2020. The primary outcome was 28-day mortality. We examined patient-level and hospital-level variables. Mixed-effects logistic regression was used to identify factors associated with interhospital variation. The median odds ratio (OR) was calculated to compare outcomes in higher- vs. lower-mortality hospitals. A gradient boosted machine algorithm was developed for individual-level mortality models. MEASUREMENTS AND MAIN RESULTS: A total of 4,019 patients were included, 1537 (38%) of whom died by 28 days. Mortality varied considerably across hospitals (0-82%). After adjustment for patient- and hospital-level domains, interhospital variation was attenuated (OR decline from 2.06 [95% CI, 1.73-2.37] to 1.22 [95% CI, 1.00-1.38]), with the greatest changes occurring with adjustment for acute physiology, socioeconomic status, and strain. For individual patients, the relative contribution of each domain to mortality risk was: acute physiology (49%), demographics and comorbidities (20%), socioeconomic status (12%), strain (9%), hospital quality (8%), and treatments (3%). CONCLUSION: There is considerable interhospital variation in mortality for critically ill patients with COVID-19, which is mostly explained by hospital-level socioeconomic status, strain, and acute physiologic differences. Individual mortality is driven mostly by patient-level factors. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Assuntos
Algoritmos , COVID-19/epidemiologia , Estado Terminal/terapia , Unidades de Terapia Intensiva/estatística & dados numéricos , Idoso , Comorbidade , Estado Terminal/epidemiologia , Feminino , Seguimentos , Mortalidade Hospitalar/tendências , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , SARS-CoV-2 , Taxa de Sobrevida/tendências , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: The Centers for Medicare and Medicaid Services provide nationwide hospital ratings that may influence reimbursement. These ratings do not account for the social risk of communities and may inadvertently penalize hospitals that service disadvantaged neighborhoods. OBJECTIVE: This study examines the relationship between neighborhood social risk factors (SRFs) and hospital ratings in Medicare's Hospital Compare Program. RESEARCH DESIGN: 2017 Medicare Hospital Compare ratings were linked with block group data from the 2015 American Community Survey to assess hospital ratings as a function of neighborhood SRFs. SUBJECTS: A total of 3608 Medicare-certified hospitals in 50 US states. MEASURES: Hospital summary scores and 7 quality group scores (100 percentile scale), including effectiveness of care, efficiency of care, hospital readmission, mortality, patient experience, safety of care, and timeliness of care. RESULTS: Lower hospital summary scores were associated with caring for neighborhoods with higher social risk, including a reduction in hospital score for every 10% of residents who reported dual-eligibility for Medicare/Medicaid [-3.3%; 95% confidence interval (CI), -4.7 to -2.0], no high-school diploma (-0.8%; 95% CI, -1.5 to -0.1), unemployment (-1.2%; 95% CI, -1.9 to -0.4), black race (-1.2%; 95% CI, -1.7 to -0.8), and high travel times to work (-2.5%; 95% CI, -3.3 to -1.6). Associations between neighborhood SRFs and hospital ratings were largest in the timeliness of care, patient experience, and hospital readmission groups; and smallest in the safety, efficiency, and effectiveness of care groups. CONCLUSIONS: Hospitals serving communities with higher social risk may have lower ratings because of neighborhood factors. Failing to account for neighborhood social risk in hospital rating systems may reinforce hidden disincentives to care for medically underserved areas in the United States.
Assuntos
Hospitais/normas , Áreas de Pobreza , Indicadores de Qualidade em Assistência à Saúde , Idoso , Centers for Medicare and Medicaid Services, U.S. , Feminino , Humanos , Masculino , Medicare , Fatores de Risco , Estados UnidosRESUMO
Many monogenic disorders, including the muscular dystrophies, display phenotypic variability despite the same disease-causing mutation. To identify genetic modifiers of muscular dystrophy and its associated cardiomyopathy, we used quantitative trait locus mapping and whole genome sequencing in a mouse model. This approach uncovered a modifier locus on chromosome 11 associated with sarcolemmal membrane damage and heart mass. Whole genome and RNA sequencing identified Anxa6, encoding annexin A6, as a modifier gene. A synonymous variant in exon 11 creates a cryptic splice donor, resulting in a truncated annexin A6 protein called ANXA6N32. Live cell imaging showed that annexin A6 orchestrates a repair zone and cap at the site of membrane disruption. In contrast, ANXA6N32 dramatically disrupted the annexin A6-rich cap and the associated repair zone, permitting membrane leak. Anxa6 is a modifier of muscular dystrophy and membrane repair after injury.
Assuntos
Anexina A6/metabolismo , Distrofia Muscular Animal/patologia , Sarcolema/metabolismo , Sarcolema/patologia , Cicatrização , Músculos Abdominais/patologia , Processamento Alternativo/genética , Animais , Anexina A6/genética , Cromossomos de Mamíferos/genética , Suscetibilidade a Doenças , Genes Modificadores , Variação Genética , Ventrículos do Coração/patologia , Espaço Intracelular/metabolismo , Membranas/patologia , Camundongos , Camundongos Endogâmicos C57BL , Distrofia Muscular Animal/genética , Tamanho do Órgão , Transporte Proteico , Locos de Características Quantitativas/genética , Cicatrização/genéticaRESUMO
The newborn heart adapts to postnatal life by shifting from a fetal glycolytic metabolism to a mitochondrial oxidative metabolism. Abcc9, an ATP-binding cassette family member, increases expression concomitant with this metabolic shift. Abcc9 encodes a membrane-associated receptor that partners with a potassium channel to become the major potassium-sensitive ATP channel in the heart. Abcc9 also encodes a smaller protein enriched in the mitochondria. We now deleted exon 5 of Abcc9 to ablate expression of both plasma membrane and mitochondria-associated Abcc9-encoded proteins, and found that the myocardium failed to acquire normal mature metabolism, resulting in neonatal cardiomyopathy. Unlike wild-type neonatal cardiomyocytes, mitochondria from Ex5 cardiomyocytes were unresponsive to the KATP agonist diazoxide, consistent with loss of KATP activity. When exposed to hydrogen peroxide to induce cell stress, Ex5 neonatal cardiomyocytes displayed a rapid collapse of mitochondria membrane potential, distinct from wild-type cardiomyocytes. Ex5 cardiomyocytes had reduced fatty acid oxidation, reduced oxygen consumption and reserve. Morphologically, Ex5 cardiac mitochondria exhibited an immature pattern with reduced cross-sectional area and intermitochondrial contacts. In the absence of Abcc9, the newborn heart fails to transition normally from fetal to mature myocardial metabolism.-Fahrenbach, J. P., Stoller, D., Kim, G., Aggarwal, N., Yerokun, B., Earley, J. U., Hadhazy, M., Shi, N.-Q., Makielski, J. C., McNally, E. M. Abcc9 is required for the transition to oxidative metabolism in the newborn heart.
Assuntos
Coração/fisiologia , Miócitos Cardíacos/metabolismo , Consumo de Oxigênio/fisiologia , Receptores de Sulfonilureias/metabolismo , Animais , Animais Recém-Nascidos , Cardiomiopatias/congênito , Membrana Celular/metabolismo , Ácidos Graxos/metabolismo , Feminino , Canais KATP/metabolismo , Masculino , Potencial da Membrana Mitocondrial/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismoRESUMO
Loss-of-function mutations in dysferlin cause muscular dystrophy, and dysferlin has been implicated in resealing membrane disruption in myofibers. Given the importance of membrane fusion in many aspects of muscle function, we studied the role of dysferlin in muscle growth. We found that dysferlin null myoblasts have a defect in myoblast-myotube fusion, resulting in smaller myotubes in culture. In vivo, dysferlin null muscle was found to have mislocalized nuclei and vacuolation. We found that myoblasts isolated from dysferlin null mice accumulate enlarged, lysosomal-associated membrane protein 2 (LAMP2)-positive lysosomes. Dysferlin null myoblasts accumulate transferrin-488, reflecting abnormal vesicular trafficking. Additionally, dysferlin null myoblasts display abnormal trafficking of the insulin-like growth factor (IGF) receptor, where the receptor is shuttled to LAMP2-positive lysosomes. We studied growth, in vivo, by infusing mice with the growth stimulant IGF1. Control IGF1-treated mice increased myofiber diameter by 30% as expected, whereas dysferlin null muscles had no response to IGF1, indicating a defect in myofiber growth. We also noted that dysferlin null fibroblasts also accumulate acidic vesicles, IGF receptor and transferrin, indicating that dysferlin is important for nonmuscle vesicular trafficking. These data implicate dysferlin in multiple membrane fusion events within the cell and suggest multiple pathways by which loss of dysferlin contributes to muscle disease.
Assuntos
Fator de Crescimento Insulin-Like I/metabolismo , Proteínas de Membrana/metabolismo , Músculo Esquelético/metabolismo , Distrofias Musculares/genética , Distrofias Musculares/metabolismo , Animais , Células Cultivadas , Vesículas Citoplasmáticas/metabolismo , Vesículas Citoplasmáticas/patologia , Modelos Animais de Doenças , Disferlina , Fator de Crescimento Insulin-Like I/farmacologia , Espaço Intracelular , Lisossomos/metabolismo , Proteínas de Membrana/genética , Camundongos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Distrofias Musculares/tratamento farmacológico , Distrofias Musculares/patologia , Mioblastos/efeitos dos fármacos , Mioblastos/metabolismo , Mioblastos/patologia , Transporte ProteicoRESUMO
Predictive analytic models leveraging machine learning methods increasingly have become vital to health care organizations hoping to improve clinical outcomes and the efficiency of care delivery for all patients. Unfortunately, predictive models could harm populations that have experienced interpersonal, institutional, and structural biases. Models learn from historically collected data that could be biased. In addition, bias impacts a model's development, application, and interpretation. We present a strategy to evaluate for and mitigate biases in machine learning models that potentially could create harm. We recommend analyzing for disparities between less and more socially advantaged populations across model performance metrics (eg, accuracy, positive predictive value), patient outcomes, and resource allocation and then identify root causes of the disparities (eg, biased data, interpretation) and brainstorm solutions to address the disparities. This strategy follows the lifecycle of machine learning models in health care, namely, identifying the clinical problem, model design, data collection, model training, model validation, model deployment, and monitoring after deployment. To illustrate this approach, we use a hypothetical case of a health system developing and deploying a machine learning model to predict the risk of mortality in 6 months for patients admitted to the hospital to target a hospital's delivery of palliative care services to those with the highest mortality risk. The core ethical concepts of equity and transparency guide our proposed framework to help ensure the safe and effective use of predictive algorithms in health care to help everyone achieve their best possible health.
Assuntos
Algoritmos , Aprendizado de Máquina , Hospitalização , Humanos , Valor Preditivo dos TestesRESUMO
Sulfonylurea receptor-containing ATP-sensitive potassium (K(ATP)) channels have been implicated in cardioprotection, but the cell type and constitution of channels responsible for this protection have not been clear. Mice deleted for the first nucleotide binding region of sulfonylurea receptor 2 (SUR2) are referred to as SUR2 null since they lack full-length SUR2 and glibenclamide-responsive K(ATP) channels in cardiac, skeletal, and smooth muscle. As previously reported, SUR2 null mice develop electrocardiographic changes of ST segment elevation that were shown to correlate with coronary artery vasospasm. Here we restored expression of the cardiomyocyte SUR2-K(ATP) channel in SUR2 null mice by generating transgenic mice with ventricular cardiomyocyte-restricted expression of SUR2A. Introduction of the cardiomyocyte SUR2A transgene into the SUR2 null background restored functional cardiac K(ATP) channels. Hearts isolated from rescued mice, referred to as MLC2A, had significantly reduced infarct size (27 ± 3% of area at risk) compared with SUR2 null mice (36 ± 3% of area at risk). Compared with SUR2 null hearts, MLC2A hearts exhibited significantly improved cardiac function during the postischemia reperfusion period primarily because of preservation of low diastolic pressures. Additionally, restoration of cardiac SUR2-K(ATP) channels significantly reduced the degree and frequency of ST segment elevation episodes in MLC2A mice. Therefore, cardioprotective mechanisms both dependent and independent of SUR2-K(ATP) channels contribute to cardiac function.
Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Eletrocardiografia , Canais KATP/metabolismo , Miócitos Cardíacos/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Receptores de Droga/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Membrana Celular/metabolismo , Vasoespasmo Coronário/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Modelos Animais , Infarto do Miocárdio/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/genética , Receptores de Droga/genética , Transdução de Sinais/fisiologia , Receptores de SulfonilureiasRESUMO
Heart failure (HF) is associated with reduced cardiac Na+ channel (SCN5A) current. We hypothesized that abnormal transcriptional regulation of this ion channel during HF could help explain the reduced current. Using human hearts explanted at the transplantation, we have identified 3 human C-terminal SCN5A mRNA splicing variants predicted to result in truncated, nonfunctional channels. As compared with normal hearts, the explanted ventricles showed an upregulation of 2 of the variants and a downregulation of the full-length mRNA transcript such that the E28A transcript represented only 48.5% (P<0.01) of the total SCN5A mRNA. This correlated with a 62.8% (P<0.01) reduction in Na+ channel protein. Lymphoblasts and skeletal muscle expressing SCN5A also showed identical C-terminal splicing variants. Variants showed reduced membrane protein and no functional current. Transfection of truncation variants into a cell line stably transfected with the full-length Na+ channel resulted in dose-dependent reductions in channel mRNA and current. Introduction of a premature truncation in the C-terminal region in a single allele of the mouse SCN5A resulted in embryonic lethality. Embryonic stem cell-derived cardiomyocytes expressing the construct showed reductions in Na+ channel-dependent electrophysiological parameters, suggesting that the presence of truncated Na+ channel mRNA at levels seen in HF is likely to be physiologically significant. In summary, chronic HF was associated with an increase in 2 truncated SCN5A variants and a decrease in the native mRNA. These splice variations may help explain a loss of Na+ channel protein and may contribute to the increased arrhythmic risk in clinical HF.
Assuntos
Processamento Alternativo , Insuficiência Cardíaca/genética , Canais de Sódio/genética , Animais , Células-Tronco Embrionárias/metabolismo , Regulação da Expressão Gênica , Variação Genética , Coração , Insuficiência Cardíaca/etiologia , Humanos , Técnicas In Vitro , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.5 , RNA Mensageiro/genética , Taxa de Sobrevida , TransfecçãoRESUMO
OBJECTIVE: To investigate whether a patient's proximity to the nurse's station or ward entrance at time of admission was associated with increased risk of adverse outcomes. METHOD: We conducted a retrospective cohort study of consecutive adult inpatients to 13 medical-surgical wards at an academic hospital from 2009 to 2013. Proximity of admission room to the nurse's station and to the ward entrance was measured using Euclidean distances. Outcomes of interest include development of critical illness (defined as cardiac arrests or transfer to an intensive care unit), inhospital mortality, and increase in length of stay (LOS). RESULTS: Of the 83,635 admissions, 4,129 developed critical illness and 1,316 died. The median LOS was 3 days. After adjusting for admission severity of illness, ward, shift, and year, we found no relationship between proximity at admission to nurse's station our outcomes. However, patients admitted to end of the ward had higher risk of developing critical illness (odds ratio [ OR] = 1.15, 95% confidence interval [CI] = [1.08, 1.23]), mortality ( OR = 1.16, 95% CI [1.03, 1.33]), and a higher LOS (13-hr increase, 95% CI [10, 15] hours) compared to patients admitted closer to the ward entrance. Similar results were observed in sensitivity analyses adjusting for isolation room patients and considering patients without room transfers in the first 48 hr. CONCLUSIONS: Our study suggests that being away from the nurse's station did not increase the risk of these adverse events in ward patients, but being farther from the ward entrance was associated with increase in risk of adverse outcomes. Patient safety can be improved by recognizing this additional risk factor.
Assuntos
Planejamento Ambiental/estatística & dados numéricos , Mortalidade Hospitalar , Pacientes Internados/estatística & dados numéricos , Tempo de Internação/estatística & dados numéricos , Postos de Enfermagem/estatística & dados numéricos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de RiscoRESUMO
The aim of this study was to determine if embryonic stem cell derived cardiomyocyte aggregates (ESdCs) can act as pacemakers in spontaneously active cardiomyocyte preparations when their connexin isoform expression is tuned toward a more sinus nodal phenotype. Using microelectrode array recordings (MEAs), we demonstrate that mouse ESdCs establish electrical coupling with spontaneously active cardiomyocyte preparations (HL-1 monolayer) and obtain pacemaker dominance. WT- and Cx43(-/-)-ESdCs comparably established intercellular coupling with cardiac host tissue (Cx43(-/-): 86% vs. WT: 91%). Although both aggregates had a 100% success rate in pacing quiescent cardiac preparations, Cx43(-/-)-ESdCs had an increased likelihood of gaining pacemaker dominance (Cx43(-/-): 40% vs. WT: 13%) in spontaneously active preparations. No differences in size, beating frequency, V(m), or differentiation were detected between WT- and Cx43(-/-)-ESdCs but the intercellular coupling resistance in Cx43(-/-)-ESdCs was significantly increased (Cx43(-/-): 1.2nS vs. WT: 14.8nS). Lack of Cx43 prolonged the time until Cx43(-/-)-ESdCs established frequency synchronization with the host tissue. It further hampered the excitation spread from the cardiomyocyte preparation into the ESdC. However rectifying excitation spread in these co-cultures could not be unequivocally identified. In summary, ESdCs can function as dominant biological pacemakers and Cx43 expression is not a prerequisite for their electrical integration. Maintenance of pacemaker dominance depends critically on the pacemaker's gap junction expression benefiting those with increased intercellular coupling resistances. Our results provide important insight into the design of biological pacemakers that will benefit the use of cardiomyocytes for cell replacement therapy.
Assuntos
Relógios Biológicos , Células-Tronco Embrionárias/citologia , Junções Comunicantes/metabolismo , Marca-Passo Artificial , Engenharia Tecidual/métodos , Animais , Engenharia Biomédica , Diferenciação Celular , Conexina 43/genética , Eletrofisiologia , Células-Tronco Embrionárias/metabolismo , Cinética , Camundongos , Camundongos Transgênicos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismoRESUMO
OBJECTIVE: Modern machine learning-based modeling methods are increasingly applied to clinical problems. One such application is in variable selection methods for predictive modeling. However, there is limited research comparing the performance of classic and modern for variable selection in clinical datasets. MATERIALS AND METHODS: We analyzed the performance of eight different variable selection methods: four regression-based methods (stepwise backward selection using p-value and AIC, Least Absolute Shrinkage and Selection Operator, and Elastic Net) and four tree-based methods (Variable Selection Using Random Forest, Regularized Random Forests, Boruta, and Gradient Boosted Feature Selection). We used two clinical datasets of different sizes, a multicenter adult clinical deterioration cohort and a single center pediatric acute kidney injury cohort. Method evaluation included measures of parsimony, variable importance, and discrimination. RESULTS: In the large, multicenter dataset, the modern tree-based Variable Selection Using Random Forest and the Gradient Boosted Feature Selection methods achieved the best parsimony. In the smaller, single-center dataset, the classic regression-based stepwise backward selection using p-value and AIC methods achieved the best parsimony. In both datasets, variable selection tended to decrease the accuracy of the random forest models and increase the accuracy of logistic regression models. CONCLUSIONS: The performance of classic regression-based and modern tree-based variable selection methods is associated with the size of the clinical dataset used. Classic regression-based variable selection methods seem to achieve better parsimony in clinical prediction problems in smaller datasets while modern tree-based methods perform better in larger datasets.
Assuntos
Aprendizado de Máquina , Adulto , Criança , Estudos de Coortes , Humanos , Modelos LogísticosRESUMO
Background: Patients with status asthmaticus admitted to the hospital contribute tremendous costs to the healthcare system. Treatment protocols directed at improving care to pediatric inpatients have improved both clinical and financial outcomes; however, there are limited data demonstrating the impact of goal-driven therapy for patients with status asthmaticus in the pediatric intensive care unit (PICU). The purpose of this initiative was to standardize care of children with status asthmaticus in the PICU to improve clinical outcomes. Materials and Methods: A goal-directed clinical pathway using a validated pediatric asthma severity score was developed. A pre-post intervention assessed patients 2-17 years of age admitted to the PICU with status asthmaticus. The effect of the protocol was measured from October 2015 to October 2016. The primary outcome was the transition time interval from continuous nebulized bronchodilator therapy to every 2 hourly intermittent treatments. Secondary outcomes related to treatment options and clinical complications were also assessed. Results: Postintervention patient (n = 124) demographics were similar to those in the preintervention group (n = 130). Compared with baseline, there was a 4.9-h decrease in the mean transition time from continuous to intermittent bronchodilator use (31.9 versus 27.0, P = 0.033) following the intervention. The mean and median hospital length of stay (LOS) was significantly decreased in the postintervention group by 14.76 h (P = 0.011) and 16.68 h (P = 0.003). There were no readmissions to the PICU in the postintervention group. The use of rescue BiPAP (Bi-level positive airway pressure ventilation) was significantly higher in the preintervention group compared with the postintervention group (42% versus 28%, P = 0.036). Conclusions: A severity-tiered, goal-driven treatment pathway for pediatric patients admitted to the PICU with status asthmaticus reduced the time required to transition from continuous to intermittent inhaled bronchodilator use. As a result, overall hospital LOS was significantly decreased with no increase in clinical complications.
RESUMO
BACKGROUND: Allergy documentation is frequently inconsistent and incomplete. The impact of this variability on subsequent treatment is not well described. OBJECTIVE: To determine how allergy documentation affects subsequent antibiotic choice. DESIGN: Retrospective, cohort study. PARTICIPANTS: 232,616 adult patients seen by 199 primary care providers (PCPs) between January 1, 2009 and January 1, 2014 at an academic medical system. MAIN MEASURES: Inter-physician variation in beta-lactam allergy documentation; antibiotic treatment following beta-lactam allergy documentation. KEY RESULTS: 15.6% of patients had a reported beta-lactam allergy. Of those patients, 39.8% had a specific allergen identified and 22.7% had allergic reaction characteristics documented. Variation between PCPs was greater than would be expected by chance (all p<0.001) in the percentage of their patients with a documented beta-lactam allergy (7.9% to 24.8%), identification of a specific allergen (e.g. amoxicillin as opposed to "penicillins") (24.0% to 58.2%) and documentation of the reaction characteristics (5.4% to 51.9%). After beta-lactam allergy documentation, patients were less likely to receive penicillins (Relative Risk [RR] 0.16 [95% Confidence Interval: 0.15-0.17]) and cephalosporins (RR 0.28 [95% CI 0.27-0.30]) and more likely to receive fluoroquinolones (RR 1.5 [95% CI 1.5-1.6]), clindamycin (RR 3.8 [95% CI 3.6-4.0]) and vancomycin (RR 5.0 [95% CI 4.3-5.8]). Among patients with beta-lactam allergy, rechallenge was more likely when a specific allergen was identified (RR 1.6 [95% CI 1.5-1.8]) and when reaction characteristics were documented (RR 2.0 [95% CI 1.8-2.2]). CONCLUSIONS: Provider documentation of beta-lactam allergy is highly variable, and details of the allergy are infrequently documented. Classification of a patient as beta-lactam allergic and incomplete documentation regarding the details of the allergy lead to beta-lactam avoidance and use of other antimicrobial agents, behaviors that may adversely impact care quality and cost.
Assuntos
Hipersensibilidade a Drogas/diagnóstico , Penicilinas/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Meta-analysis of gene expression array databases has the potential to reveal information about gene function. The identification of gene-gene interactions may be inferred from gene expression information but such meta-analysis is often limited to a single microarray platform. To address this limitation, we developed a gene-centered approach to analyze differential expression across thousands of gene expression experiments and created the CO-Regulation Database (CORD) to determine which genes are correlated with a queried gene. RESULTS: Using the GEO and ArrayExpress database, we analyzed over 120,000 group by group experiments from gene microarrays to determine the correlating genes for over 30,000 different genes or hypothesized genes. CORD output data is presented for sample queries with focus on genes with well-known interaction networks including p16 (CDKN2A), vimentin (VIM), MyoD (MYOD1). CDKN2A, VIM, and MYOD1 all displayed gene correlations consistent with known interacting genes. CONCLUSIONS: We developed a facile, web-enabled program to determine gene-gene correlations across different gene expression microarray platforms. Using well-characterized genes, we illustrate how CORD's identification of co-expressed genes contributes to a better understanding a gene's potential function. The website is found at http://cord-db.org.
Assuntos
Perfilação da Expressão Gênica , Quinase 4 Dependente de Ciclina/genética , Bases de Dados Genéticas , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Genes p16 , Humanos , Proteína MyoD/genética , Proteína MyoD/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Software , Transcriptoma , Vimentina/genética , Vimentina/metabolismoRESUMO
BACKGROUND: Cardiomyopathy is highly heritable but genetically diverse. At present, genetic testing for cardiomyopathy uses targeted sequencing to simultaneously assess the coding regions of >50 genes. New genes are routinely added to panels to improve the diagnostic yield. With the anticipated $1000 genome, it is expected that genetic testing will shift toward comprehensive genome sequencing accompanied by targeted gene analysis. Therefore, we assessed the reliability of whole genome sequencing and targeted analysis to identify cardiomyopathy variants in 11 subjects with cardiomyopathy. METHODS AND RESULTS: Whole genome sequencing with an average of 37× coverage was combined with targeted analysis focused on 204 genes linked to cardiomyopathy. Genetic variants were scored using multiple prediction algorithms combined with frequency data from public databases. This pipeline yielded 1 to 14 potentially pathogenic variants per individual. Variants were further analyzed using clinical criteria and segregation analysis, where available. Three of 3 previously identified primary mutations were detected by this analysis. In 6 subjects for whom the primary mutation was previously unknown, we identified mutations that segregated with disease, had clinical correlates, and had additional pathological correlation to provide evidence for causality. For 2 subjects with previously known primary mutations, we identified additional variants that may act as modifiers of disease severity. In total, we identified the likely pathological mutation in 9 of 11 (82%) subjects. CONCLUSIONS: These pilot data demonstrate that ≈30 to 40× coverage whole genome sequencing combined with targeted analysis is feasible and sensitive to identify rare variants in cardiomyopathy-associated genes.
Assuntos
Cardiomiopatias/diagnóstico , Genoma Humano , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Adulto , Algoritmos , Cardiomiopatias/economia , Cardiomiopatias/genética , Criança , Bases de Dados Genéticas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Proteínas com Domínio LIM/genética , Pessoa de Meia-Idade , Cadeias Pesadas de Miosina/genética , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Linhagem , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Adulto JovemAssuntos
Hospitalização/economia , Telemetria/economia , Telemetria/estatística & dados numéricos , Procedimentos Desnecessários/economia , Cateterismo Urinário/economia , Cateterismo Urinário/estatística & dados numéricos , Controle de Custos , Técnicas de Apoio para a Decisão , Humanos , Melhoria de QualidadeRESUMO
BACKGROUND: Hypertrophic cardiomyopathy and dilated cardiomyopathy arise from mutations in genes encoding sarcomere proteins including MYH7, MYBPC3, and TTN. Genetic diagnosis of cardiomyopathy relies on complete sequencing of the gene coding regions, and most pathogenic variation is rare. The 1000 Genomes Project is an ongoing consortium designed to deliver whole genome sequence information from an ethnically diverse population and, therefore, is a rich source to determine both common and rare genetic variants. METHODS AND RESULTS: We queried the 1000 Genomes Project database of 1092 individuals for exonic variants within 3 sarcomere genes MHY7, MYBPC3, and TTN. We focused our analysis on protein-altering variation, including nonsynonymous single nucleotide polymorphisms, insertion/deletion polymorphisms, or splice site altering variants. We identified known and predicted pathogenic variation in MYBPC3 and MYH7 at a higher frequency than what would be expected based on the known prevalence of cardiomyopathy. We also found substantial variation, including protein-disrupting sequences, in TTN. CONCLUSIONS: Cardiomyopathy is a genetically heterogeneous disorder caused by mutations in multiple genes. The frequency of predicted pathogenic protein-altering variation in cardiomyopathy genes suggests that many of these variants may be insufficient to cause disease on their own but may modify phenotype in a genetically susceptible host. This is suggested by the high prevalence of TTN insertion/deletions in the 1000 Genomes Project cohort. Given the possibility of additional genetic variants that modify the phenotype of a primary driver mutation, broad-based genetic testing should be employed.