RESUMO
OBJECTIVE: For multi-center heterogeneous Real-World Data (RWD) with time-to-event outcomes and high-dimensional features, we propose the SurvMaximin algorithm to estimate Cox model feature coefficients for a target population by borrowing summary information from a set of health care centers without sharing patient-level information. MATERIALS AND METHODS: For each of the centers from which we want to borrow information to improve the prediction performance for the target population, a penalized Cox model is fitted to estimate feature coefficients for the center. Using estimated feature coefficients and the covariance matrix of the target population, we then obtain a SurvMaximin estimated set of feature coefficients for the target population. The target population can be an entire cohort comprised of all centers, corresponding to federated learning, or a single center, corresponding to transfer learning. RESULTS: Simulation studies and a real-world international electronic health records application study, with 15 participating health care centers across three countries (France, Germany, and the U.S.), show that the proposed SurvMaximin algorithm achieves comparable or higher accuracy compared with the estimator using only the information of the target site and other existing methods. The SurvMaximin estimator is robust to variations in sample sizes and estimated feature coefficients between centers, which amounts to significantly improved estimates for target sites with fewer observations. CONCLUSIONS: The SurvMaximin method is well suited for both federated and transfer learning in the high-dimensional survival analysis setting. SurvMaximin only requires a one-time summary information exchange from participating centers. Estimated regression vectors can be very heterogeneous. SurvMaximin provides robust Cox feature coefficient estimates without outcome information in the target population and is privacy-preserving.
Assuntos
Algoritmos , Registros Eletrônicos de Saúde , Humanos , Privacidade , Modelos de Riscos Proporcionais , Análise de SobrevidaRESUMO
BACKGROUND: Many countries have experienced 2 predominant waves of COVID-19-related hospitalizations. Comparing the clinical trajectories of patients hospitalized in separate waves of the pandemic enables further understanding of the evolving epidemiology, pathophysiology, and health care dynamics of the COVID-19 pandemic. OBJECTIVE: In this retrospective cohort study, we analyzed electronic health record (EHR) data from patients with SARS-CoV-2 infections hospitalized in participating health care systems representing 315 hospitals across 6 countries. We compared hospitalization rates, severe COVID-19 risk, and mean laboratory values between patients hospitalized during the first and second waves of the pandemic. METHODS: Using a federated approach, each participating health care system extracted patient-level clinical data on their first and second wave cohorts and submitted aggregated data to the central site. Data quality control steps were adopted at the central site to correct for implausible values and harmonize units. Statistical analyses were performed by computing individual health care system effect sizes and synthesizing these using random effect meta-analyses to account for heterogeneity. We focused the laboratory analysis on C-reactive protein (CRP), ferritin, fibrinogen, procalcitonin, D-dimer, and creatinine based on their reported associations with severe COVID-19. RESULTS: Data were available for 79,613 patients, of which 32,467 were hospitalized in the first wave and 47,146 in the second wave. The prevalence of male patients and patients aged 50 to 69 years decreased significantly between the first and second waves. Patients hospitalized in the second wave had a 9.9% reduction in the risk of severe COVID-19 compared to patients hospitalized in the first wave (95% CI 8.5%-11.3%). Demographic subgroup analyses indicated that patients aged 26 to 49 years and 50 to 69 years; male and female patients; and black patients had significantly lower risk for severe disease in the second wave than in the first wave. At admission, the mean values of CRP were significantly lower in the second wave than in the first wave. On the seventh hospital day, the mean values of CRP, ferritin, fibrinogen, and procalcitonin were significantly lower in the second wave than in the first wave. In general, countries exhibited variable changes in laboratory testing rates from the first to the second wave. At admission, there was a significantly higher testing rate for D-dimer in France, Germany, and Spain. CONCLUSIONS: Patients hospitalized in the second wave were at significantly lower risk for severe COVID-19. This corresponded to mean laboratory values in the second wave that were more likely to be in typical physiological ranges on the seventh hospital day compared to the first wave. Our federated approach demonstrated the feasibility and power of harmonizing heterogeneous EHR data from multiple international health care systems to rapidly conduct large-scale studies to characterize how COVID-19 clinical trajectories evolve.
Assuntos
COVID-19 , Pandemias , Adulto , Idoso , Feminino , Hospitalização , Hospitais , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , SARS-CoV-2RESUMO
[This corrects the article DOI: 10.2196/31400.].
RESUMO
With the rapid growth of publicly available high-throughput transcriptomic data, there is increasing recognition that large sets of such data can be mined to better understand disease states and mechanisms. Prior gene expression analyses, both large and small, have been dichotomous in nature, in which phenotypes are compared using clearly defined controls. Such approaches may require arbitrary decisions about what are considered "normal" phenotypes, and what each phenotype should be compared to. Instead, we adopt a holistic approach in which we characterize phenotypes in the context of a myriad of tissues and diseases. We introduce scalable methods that associate expression patterns to phenotypes in order both to assign phenotype labels to new expression samples and to select phenotypically meaningful gene signatures. By using a nonparametric statistical approach, we identify signatures that are more precise than those from existing approaches and accurately reveal biological processes that are hidden in case vs. control studies. Employing a comprehensive perspective on expression, we show how metastasized tumor samples localize in the vicinity of the primary site counterparts and are overenriched for those phenotype labels. We find that our approach provides insights into the biological processes that underlie differences between tissues and diseases beyond those identified by traditional differential expression analyses. Finally, we provide an online resource (http://concordia.csail.mit.edu) for mapping users' gene expression samples onto the expression landscape of tissue and disease.
Assuntos
Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Estatística como Assunto , Marcadores Genéticos , Humanos , Metástase Neoplásica/genética , Especificidade de Órgãos/genética , Fenótipo , Reprodutibilidade dos Testes , Transcriptoma/genéticaRESUMO
BACKGROUND: With an increasing number of therapeutic options available for the management of ulcerative colitis (UC), the variability in treatment and prescribing patterns is not well known. While recent guidelines have provided updates on how these therapeutic options should be used, patterns of long-term use of these drugs over the past 2 decades remain unclear. METHODS: We analyzed a retrospective, nationwide cohort of more than 1.7 million prescriptions for trends in prescribing behaviors and to evaluate practices suggested in guidelines relating to ordering biologics, step-up therapy, and combination therapy. The primary outcome was 30-day steroid-free remission and secondary outcomes included hospitalization, cost, and additional steroid usage. A pipeline was created to identify cohorts of patients under active UC medical management grouped by prescribing strategies to evaluate comparative outcomes between strategies. Cox proportional hazards and multivariate regression models were utilized to assess postexposure outcomes and adjust for confounders. RESULTS: Among 6 major drug categories, we noted major baseline differences in patient characteristics at first exposure corresponding to disease activity. We noted earlier use of biologics in patient trajectories (762 days earlier relative to UC diagnosis, 2018 vs 2008; P < .001) and greater overall use of biologics over time (2.53× more in 2018 vs 2008; P < .00001) . Among biologic-naive patients, adalimumab was associated with slightly lower rates of remission compared with infliximab or vedolizumab (odds ratio, 0.92; P < .005). Comparisons of patients with early biologic initiation to patients who transitioned to biologics from 5-aminosalicylic acid suggest lower steroid consumption for early biologic initiation (-761 mg prednisone; P < .001). Combination thiopurine-biologic therapy was associated with higher odds of remission compared with biologic monotherapy (odds ratio, 1.36; P = .01). CONCLUSIONS: As biologic drugs have become increasingly available for UC management, they have increasingly been used at earlier stages of disease management. Large-scale analyses of prescribing behaviors provide evidence supporting early use of biologics compared with step-up therapy and use of thiopurine and biologic combination therapy.
Population-scale analysis reveals patterns in prescribing trends for ulcerative colitis management. Findings include (1) earlier use of biologics in patient trajectories, (2) associations of step-up therapy with higher corticosteroid exposure, and (3) association of combination therapy with positive patient outcomes.
Assuntos
Produtos Biológicos , Colite Ulcerativa , Humanos , Colite Ulcerativa/tratamento farmacológico , Estudos Retrospectivos , Infliximab/uso terapêutico , Adalimumab/uso terapêutico , Fatores Biológicos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Produtos Biológicos/uso terapêuticoRESUMO
Given the growing number of prediction algorithms developed to predict COVID-19 mortality, we evaluated the transportability of a mortality prediction algorithm using a multi-national network of healthcare systems. We predicted COVID-19 mortality using baseline commonly measured laboratory values and standard demographic and clinical covariates across healthcare systems, countries, and continents. Specifically, we trained a Cox regression model with nine measured laboratory test values, standard demographics at admission, and comorbidity burden pre-admission. These models were compared at site, country, and continent level. Of the 39,969 hospitalized patients with COVID-19 (68.6% male), 5717 (14.3%) died. In the Cox model, age, albumin, AST, creatine, CRP, and white blood cell count are most predictive of mortality. The baseline covariates are more predictive of mortality during the early days of COVID-19 hospitalization. Models trained at healthcare systems with larger cohort size largely retain good transportability performance when porting to different sites. The combination of routine laboratory test values at admission along with basic demographic features can predict mortality in patients hospitalized with COVID-19. Importantly, this potentially deployable model differs from prior work by demonstrating not only consistent performance but also reliable transportability across healthcare systems in the US and Europe, highlighting the generalizability of this model and the overall approach.
RESUMO
OBJECTIVE: To assess changes in international mortality rates and laboratory recovery rates during hospitalisation for patients hospitalised with SARS-CoV-2 between the first wave (1 March to 30 June 2020) and the second wave (1 July 2020 to 31 January 2021) of the COVID-19 pandemic. DESIGN, SETTING AND PARTICIPANTS: This is a retrospective cohort study of 83 178 hospitalised patients admitted between 7 days before or 14 days after PCR-confirmed SARS-CoV-2 infection within the Consortium for Clinical Characterization of COVID-19 by Electronic Health Record, an international multihealthcare system collaborative of 288 hospitals in the USA and Europe. The laboratory recovery rates and mortality rates over time were compared between the two waves of the pandemic. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was all-cause mortality rate within 28 days after hospitalisation stratified by predicted low, medium and high mortality risk at baseline. The secondary outcome was the average rate of change in laboratory values during the first week of hospitalisation. RESULTS: Baseline Charlson Comorbidity Index and laboratory values at admission were not significantly different between the first and second waves. The improvement in laboratory values over time was faster in the second wave compared with the first. The average C reactive protein rate of change was -4.72 mg/dL vs -4.14 mg/dL per day (p=0.05). The mortality rates within each risk category significantly decreased over time, with the most substantial decrease in the high-risk group (42.3% in March-April 2020 vs 30.8% in November 2020 to January 2021, p<0.001) and a moderate decrease in the intermediate-risk group (21.5% in March-April 2020 vs 14.3% in November 2020 to January 2021, p<0.001). CONCLUSIONS: Admission profiles of patients hospitalised with SARS-CoV-2 infection did not differ greatly between the first and second waves of the pandemic, but there were notable differences in laboratory improvement rates during hospitalisation. Mortality risks among patients with similar risk profiles decreased over the course of the pandemic. The improvement in laboratory values and mortality risk was consistent across multiple countries.
Assuntos
COVID-19 , Pandemias , Hospitalização , Humanos , Estudos Retrospectivos , SARS-CoV-2RESUMO
Systemic corticosteroids are not recommended to treat children with acute respiratory tract infections (ARTIs). Using data from a national commercial health care company, we found that corticosteroid treatment occurred in 3.2% of ARTI encounters. The adjusted odds of corticosteroid treatment were highest for bronchitis/bronchiolitis, in emergency departments, and in the South.
Assuntos
Bronquiolite , Infecções Respiratórias , Doença Aguda , Corticosteroides/uso terapêutico , Antibacterianos/uso terapêutico , Bronquiolite/tratamento farmacológico , Criança , Humanos , Infecções Respiratórias/tratamento farmacológicoRESUMO
OBJECTIVE: Large amounts of health data are becoming available for biomedical research. Synthesizing information across databases may capture more comprehensive pictures of patient health and enable novel research studies. When no gold standard mappings between patient records are available, researchers may probabilistically link records from separate databases and analyze the linked data. However, previous linked data inference methods are constrained to certain linkage settings and exhibit low power. Here, we present ATLAS, an automated, flexible, and robust association testing algorithm for probabilistically linked data. MATERIALS AND METHODS: Missing variables are imputed at various thresholds using a weighted average method that propagates uncertainty from probabilistic linkage. Next, estimated effect sizes are obtained using a generalized linear model. ATLAS then conducts the threshold combination test by optimally combining P values obtained from data imputed at varying thresholds using Fisher's method and perturbation resampling. RESULTS: In simulations, ATLAS controls for type I error and exhibits high power compared to previous methods. In a real-world genetic association study, meta-analysis of ATLAS-enabled analyses on a linked cohort with analyses using an existing cohort yielded additional significant associations between rheumatoid arthritis genetic risk score and laboratory biomarkers. DISCUSSION: Weighted average imputation weathers false matches and increases contribution of true matches to mitigate linkage error-induced bias. The threshold combination test avoids arbitrarily choosing a threshold to rule a match, thus automating linked data-enabled analyses and preserving power. CONCLUSION: ATLAS promises to enable novel and powerful research studies using linked data to capitalize on all available data sources.
Assuntos
Algoritmos , Registro Médico Coordenado , Viés , Bases de Dados Factuais , Testes Diagnósticos de Rotina , HumanosRESUMO
Objectives: To perform an international comparison of the trajectory of laboratory values among hospitalized patients with COVID-19 who develop severe disease and identify optimal timing of laboratory value collection to predict severity across hospitals and regions. Design: Retrospective cohort study. Setting: The Consortium for Clinical Characterization of COVID-19 by EHR (4CE), an international multi-site data-sharing collaborative of 342 hospitals in the US and in Europe. Participants: Patients hospitalized with COVID-19, admitted before or after PCR-confirmed result for SARS-CoV-2. Primary and secondary outcome measures: Patients were categorized as "ever-severe" or "never-severe" using the validated 4CE severity criteria. Eighteen laboratory tests associated with poor COVID-19-related outcomes were evaluated for predictive accuracy by area under the curve (AUC), compared between the severity categories. Subgroup analysis was performed to validate a subset of laboratory values as predictive of severity against a published algorithm. A subset of laboratory values (CRP, albumin, LDH, neutrophil count, D-dimer, and procalcitonin) was compared between North American and European sites for severity prediction. Results: Of 36,447 patients with COVID-19, 19,953 (43.7%) were categorized as ever-severe. Most patients (78.7%) were 50 years of age or older and male (60.5%). Longitudinal trajectories of CRP, albumin, LDH, neutrophil count, D-dimer, and procalcitonin showed association with disease severity. Significant differences of laboratory values at admission were found between the two groups. With the exception of D-dimer, predictive discrimination of laboratory values did not improve after admission. Sub-group analysis using age, D-dimer, CRP, and lymphocyte count as predictive of severity at admission showed similar discrimination to a published algorithm (AUC=0.88 and 0.91, respectively). Both models deteriorated in predictive accuracy as the disease progressed. On average, no difference in severity prediction was found between North American and European sites. Conclusions: Laboratory test values at admission can be used to predict severity in patients with COVID-19. Prediction models show consistency across international sites highlighting the potential generalizability of these models.
RESUMO
We leveraged the largely untapped resource of electronic health record data to address critical clinical and epidemiological questions about Coronavirus Disease 2019 (COVID-19). To do this, we formed an international consortium (4CE) of 96 hospitals across five countries (www.covidclinical.net). Contributors utilized the Informatics for Integrating Biology and the Bedside (i2b2) or Observational Medical Outcomes Partnership (OMOP) platforms to map to a common data model. The group focused on temporal changes in key laboratory test values. Harmonized data were analyzed locally and converted to a shared aggregate form for rapid analysis and visualization of regional differences and global commonalities. Data covered 27,584 COVID-19 cases with 187,802 laboratory tests. Case counts and laboratory trajectories were concordant with existing literature. Laboratory tests at the time of diagnosis showed hospital-level differences equivalent to country-level variation across the consortium partners. Despite the limitations of decentralized data generation, we established a framework to capture the trajectory of COVID-19 disease in patients and their response to interventions.
RESUMO
We develop an algorithm for probabilistic linkage of de-identified research datasets at the patient level, when only diagnosis codes with discrepancies and no personal health identifiers such as name or date of birth are available. It relies on Bayesian modelling of binarized diagnosis codes, and provides a posterior probability of matching for each patient pair, while considering all the data at once. Both in our simulation study (using an administrative claims dataset for data generation) and in two real use-cases linking patient electronic health records from a large tertiary care network, our method exhibits good performance and compares favourably to the standard baseline Fellegi-Sunter algorithm. We propose a scalable, fast and efficient open-source implementation in the ludic R package available on CRAN, which also includes the anonymized diagnosis code data from our real use-case. This work suggests it is possible to link de-identified research databases stripped of any personal health identifiers using only diagnosis codes, provided sufficient information is shared between the data sources.
Assuntos
Algoritmos , Conjuntos de Dados como Assunto , Armazenamento e Recuperação da Informação/métodos , Teorema de Bayes , Confidencialidade , Registros Eletrônicos de Saúde , HumanosRESUMO
BACKGROUND: Presenting features of inflammatory bowel disease (IBD) are non-specific. We hypothesized that mRNA profiles could (1) identify genes and pathways involved in disease pathogenesis; (2) identify a molecular signature that differentiates IBD from other conditions; (3) provide insight into systemic and colon-specific dysregulation through study of the concordance of the gene expression. METHODS: Children (8-18 years) were prospectively recruited at the time of diagnostic colonoscopy for possible IBD. We used transcriptome-wide mRNA profiling to study gene expression in colon biopsies and paired whole blood samples. Using blood mRNA measurements, we fit a regression model for disease state prediction that was validated in an independent test set of adult subjects (GSE3365). RESULTS: Ninety-eight children were recruited [39 Crohn's disease, 18 ulcerative colitis, 2 IBDU, 39 non-IBD]. There were 1,118 significantly differentially (IBD vs non-IBD) expressed genes in colon tissue, and 880 in blood. The direction of relative change in expression was concordant for 106/112 genes differentially expressed in both tissue types. The regression model from the blood mRNA measurements distinguished IBD vs non-IBD disease status in the independent test set with 80% accuracy using only 6 genes. The overlap of 5 immune and metabolic pathways in the two tissue types was significant (p<0.001). CONCLUSIONS: Blood and colon tissue from patients with IBD share a common transcriptional profile dominated by immune and metabolic pathways. Our results suggest that peripheral blood expression levels of as few as 6 genes (IL7R, UBB, TXNIP, S100A8, ALAS2, and SLC2A3) may distinguish patients with IBD from non-IBD.
Assuntos
Colite Ulcerativa/diagnóstico , Colo/patologia , Doença de Crohn/diagnóstico , Perfilação da Expressão Gênica/métodos , Mucosa Intestinal/patologia , Adolescente , Biomarcadores/sangue , Biomarcadores/metabolismo , Biópsia , Criança , Colite Ulcerativa/sangue , Colite Ulcerativa/patologia , Colo/diagnóstico por imagem , Colonoscopia , Doença de Crohn/sangue , Doença de Crohn/patologia , Estudos de Viabilidade , Feminino , Humanos , Mucosa Intestinal/diagnóstico por imagem , Masculino , Estudos Prospectivos , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Accidental falls among people aged 65 years and older caused approximately 2,700,000 injuries, 27,000 deaths, and cost more than 34 billion dollars in the US annually in recent years. Here, we derive and validate a predictive model for falls based on a retrospective cohort of those 65 years and older. METHODS: Insurance claims from a 1-year observational period were used to predict a fall-related claim in the following 2 years. The predictive model takes into account a person's age, sex, prescriptions, and diagnoses. Through random assignment, half of the people had their claims used to derive the model, while the remaining people had their claims used to validate the model. RESULTS: Of 120,881 individuals with Aetna health insurance coverage, 12,431 (10.3%) members fell. During validation, people were risk stratified across 20 levels, where those in the highest risk stratum had 10.5 times the risk as those in the lowest stratum (33.1% vs 3.1%). CONCLUSIONS: Using only insurance claims, individuals in this large cohort at high risk of falls could be readily identified up to 2 years in advance. Although external validation is needed, the findings support the use of the model to better target interventions.
Assuntos
Acidentes por Quedas/estatística & dados numéricos , Revisão da Utilização de Seguros , Medição de Risco/métodos , Idoso , Feminino , Humanos , Masculino , Modelos Estatísticos , Estudos RetrospectivosRESUMO
OBJECTIVES: We sought to characterize the population of patients seeking care at multiple emergency departments (EDs) and to quantify the proportion of all ED visits and costs accounted for by these patients. METHODS: We performed a retrospective, cohort study of deidentified insurance claims for privately insured patients with one of more ED visits between 2010 and 2016. We measured the number of EDs visited by each patient and determined the overall proportion of all ED visits and ED costs accounted for by patients who visit multiple EDs. We identified factors associated with visiting multiple EDs. RESULTS: A total of 8,651,716 patients made 16,390,676 ED visits over the study period, accounting for $26,102,831,740 in ED costs. A significant minority (20.5%) of patients visited more than one ED over the study period. However, these patients accounted for a disproportionate amount of all ED visits (41.4%) and all ED costs (39.2%). A small proportion (0.4%) of patients visited five or more EDs but accounted for 2.8% of ED visits and costs. Among patients with two ED visits within 30 days, 32% were to different EDs. Having at least one ED visit for mental health or substance abuse-related diagnosis was associated with increased odds of visiting multiple EDs. CONCLUSIONS: A substantial minority of patients visit multiple EDs, but account for a disproportionate burden of overall ED utilization and costs. Future work should evaluate the impact of visiting multiple EDs on care utilization and outcomes and explore systems for improving access to patient records across care centers.
Assuntos
Serviço Hospitalar de Emergência/economia , Serviço Hospitalar de Emergência/estatística & dados numéricos , Hospitais/estatística & dados numéricos , Uso Excessivo dos Serviços de Saúde/economia , Uso Excessivo dos Serviços de Saúde/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Transtornos Mentais/economia , Transtornos Mentais/epidemiologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Transtornos Relacionados ao Uso de Substâncias/economia , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Estados Unidos/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Autism spectrum disorder (ASD) is a common neurodevelopmental disorder that tends to co-occur with other diseases, including asthma, inflammatory bowel disease, infections, cerebral palsy, dilated cardiomyopathy, muscular dystrophy, and schizophrenia. However, the molecular basis of this co-occurrence, and whether it is due to a shared component that influences both pathophysiology and environmental triggering of illness, has not been elucidated. To address this, we deploy a three-tiered transcriptomic meta-analysis that functions at the gene, pathway, and disease levels across ASD and its co-morbidities. RESULTS: Our analysis reveals a novel shared innate immune component between ASD and all but three of its co-morbidities that were examined. In particular, we find that the Toll-like receptor signaling and the chemokine signaling pathways, which are key pathways in the innate immune response, have the highest shared statistical significance. Moreover, the disease genes that overlap these two innate immunity pathways can be used to classify the cases of ASD and its co-morbidities vs. controls with at least 70 % accuracy. CONCLUSIONS: This finding suggests that a neuropsychiatric condition and the majority of its non-brain-related co-morbidities share a dysregulated signal that serves as not only a common genetic basis for the diseases but also as a link to environmental triggers. It also raises the possibility that treatment and/or prophylaxis used for disorders of innate immunity may be successfully used for ASD patients with immune-related phenotypes.
Assuntos
Transtorno do Espectro Autista/genética , Comorbidade , Imunidade Inata/genética , Transcriptoma/genética , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/imunologia , Perfilação da Expressão Gênica , Humanos , Transdução de Sinais/genética , Transcriptoma/imunologiaRESUMO
In biomedical informatics, assigning drug codes to categories is a common step in the analysis pipeline. Unfortunately, incomplete mappings are the norm rather than the exception with coverage values less than 85% not uncommon. Here, we perform this linking task on a nationwide insurance claims database with over 13 million members who were dispensed, according to National Drug Codes (NDCs), over 50,000 unique product forms of medication. The chosen approach employs Cerner Multum's VantageRx and the U.S. National Library of Medicine's RxMix. As a result, 94.0% of the NDCs were successfully mapped to categories used by common drug terminologies, e.g., Anatomical Therapeutic Chemical (ATC). Implemented as an SQL database and scripts, the approach is generic and can be setup for a new data set in a few hours. Thus, the method is a viable option for large-scale drug classification.
RESUMO
BACKGROUND: Fragile X syndrome (FXS) is a neurodevelopmental disorder whose biochemical manifestations involve dysregulation of mGluR5-dependent pathways, which are widely modeled using cultured neurons. In vitro phenotypes in cultured neurons using standard morphological, functional, and chemical approaches have demonstrated considerable variability. Here, we study transcriptomes obtained in situ in the intact brain tissues of a murine model of FXS to see how they reflect the in vitro state. METHODS: We used genome-wide mRNA expression profiling as a robust characterization tool for studying differentially expressed pathways in fragile X mental retardation 1 (Fmr1) knockout (KO) and wild-type (WT) murine primary neuronal cultures and in embryonic hippocampal and cortical murine tissue. To study the developmental trajectory and to relate mouse model data to human data, we used an expression map of human development to plot murine differentially expressed genes in KO/WT cultures and brain. RESULTS: We found that transcriptomes from cell cultures showed a stronger signature of Fmr1KO than whole tissue transcriptomes. We observed an over-representation of immunological signaling pathways in embryonic Fmr1KO cortical and hippocampal tissues and over-represented mGluR5-downstream signaling pathways in Fmr1KO cortical and hippocampal primary cultures. Genes whose expression was up-regulated in Fmr1KO murine cultures tended to peak early in human development, whereas differentially expressed genes in embryonic cortical and hippocampal tissues clustered with genes expressed later in human development. CONCLUSIONS: The transcriptional profile in brain tissues primarily centered on immunological mechanisms, whereas the profiles from cell cultures showed defects in neuronal activity. We speculate that the isolation and culturing of neurons caused a shift in neurological transcriptome towards a "juvenile" or "de-differentiated" state. Moreover, cultured neurons lack the close coupling with glia that might be responsible for the immunological phenotype in the intact brain. Our results suggest that cultured cells may recapitulate an early phase of the disease, which is also less obscured with a consequent "immunological" phenotype and in vivo compensatory mechanisms observed in the embryonic brain. Together, these results suggest that the transcriptome of cultured primary neuronal cells, in comparison to whole brain tissue, more robustly demonstrated the difference between Fmr1KO and WT mice and might reveal a molecular phenotype, which is typically hidden by compensatory mechanisms present in vivo. Moreover, cultures might be useful for investigating the perturbed pathways in early human brain development and genes previously implicated in autism.
RESUMO
The elucidation of disease etiologies and establishment of robust, scalable, high-throughput screening assays for autism spectrum disorders (ASDs) have been impeded by both inaccessibility of disease-relevant neuronal tissue and the genetic heterogeneity of the disorder. Neuronal cells derived from induced pluripotent stem cells (iPSCs) from autism patients may circumvent these obstacles and serve as relevant cell models. To date, derived cells are characterized and screened by assessing their neuronal phenotypes. These characterizations are often etiology-specific or lack reproducibility and stability. In this review, we present an overview of efforts to study iPSC-derived neurons as a model for autism, and we explore the plausibility of gene expression profiling as a reproducible and stable disease marker.
Assuntos
Transtorno Autístico/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Neurônios/metabolismo , Animais , Transtorno Autístico/tratamento farmacológico , Biomarcadores , Técnicas de Cultura de Células , Diferenciação Celular/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Neurônios/citologia , Fenótipo , TranscriptomaRESUMO
BACKGROUND: Medication nonadherence costs $300 billion annually in the US. Medicare Advantage plans have a financial incentive to increase medication adherence among members because the Centers for Medicare and Medicaid Services (CMS) now awards substantive bonus payments to such plans, based in part on population adherence to chronic medications. We sought to build an individualized surveillance model that detects early which beneficiaries will fall below the CMS adherence threshold. METHODS: This was a retrospective study of over 210,000 beneficiaries initiating statins, in a database of private insurance claims, from 2008-2011. A logistic regression model was constructed to use statin adherence from initiation to day 90 to predict beneficiaries who would not meet the CMS measure of proportion of days covered 0.8 or above, from day 91 to 365. The model controlled for 15 additional characteristics. In a sensitivity analysis, we varied the number of days of adherence data used for prediction. RESULTS: Lower adherence in the first 90 days was the strongest predictor of one-year nonadherence, with an odds ratio of 25.0 (95% confidence interval 23.7-26.5) for poor adherence at one year. The model had an area under the receiver operating characteristic curve of 0.80. Sensitivity analysis revealed that predictions of comparable accuracy could be made only 40 days after statin initiation. When members with 30-day supplies for their first statin fill had predictions made at 40 days, and members with 90-day supplies for their first fill had predictions made at 100 days, poor adherence could be predicted with 86% positive predictive value. CONCLUSIONS: To preserve their Medicare Star ratings, plan managers should identify or develop effective programs to improve adherence. An individualized surveillance approach can be used to target members who would most benefit, recognizing the tradeoff between improved model performance over time and the advantage of earlier detection.