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1.
Lancet ; 394(10211): 1816-1826, 2019 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-31668726

RESUMO

BACKGROUND: Uncertainty remains about the optimal monotherapy for hypertension, with current guidelines recommending any primary agent among the first-line drug classes thiazide or thiazide-like diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, dihydropyridine calcium channel blockers, and non-dihydropyridine calcium channel blockers, in the absence of comorbid indications. Randomised trials have not further refined this choice. METHODS: We developed a comprehensive framework for real-world evidence that enables comparative effectiveness and safety evaluation across many drugs and outcomes from observational data encompassing millions of patients, while minimising inherent bias. Using this framework, we did a systematic, large-scale study under a new-user cohort design to estimate the relative risks of three primary (acute myocardial infarction, hospitalisation for heart failure, and stroke) and six secondary effectiveness and 46 safety outcomes comparing all first-line classes across a global network of six administrative claims and three electronic health record databases. The framework addressed residual confounding, publication bias, and p-hacking using large-scale propensity adjustment, a large set of control outcomes, and full disclosure of hypotheses tested. FINDINGS: Using 4·9 million patients, we generated 22 000 calibrated, propensity-score-adjusted hazard ratios (HRs) comparing all classes and outcomes across databases. Most estimates revealed no effectiveness differences between classes; however, thiazide or thiazide-like diuretics showed better primary effectiveness than angiotensin-converting enzyme inhibitors: acute myocardial infarction (HR 0·84, 95% CI 0·75-0·95), hospitalisation for heart failure (0·83, 0·74-0·95), and stroke (0·83, 0·74-0·95) risk while on initial treatment. Safety profiles also favoured thiazide or thiazide-like diuretics over angiotensin-converting enzyme inhibitors. The non-dihydropyridine calcium channel blockers were significantly inferior to the other four classes. INTERPRETATION: This comprehensive framework introduces a new way of doing observational health-care science at scale. The approach supports equivalence between drug classes for initiating monotherapy for hypertension-in keeping with current guidelines, with the exception of thiazide or thiazide-like diuretics superiority to angiotensin-converting enzyme inhibitors and the inferiority of non-dihydropyridine calcium channel blockers. FUNDING: US National Science Foundation, US National Institutes of Health, Janssen Research & Development, IQVIA, South Korean Ministry of Health & Welfare, Australian National Health and Medical Research Council.


Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Adolescente , Adulto , Idoso , Antagonistas de Receptores de Angiotensina/efeitos adversos , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/efeitos adversos , Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Criança , Estudos de Coortes , Pesquisa Comparativa da Efetividade/métodos , Bases de Dados Factuais , Diuréticos/efeitos adversos , Diuréticos/uso terapêutico , Medicina Baseada em Evidências/métodos , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/prevenção & controle , Humanos , Hipertensão/complicações , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/prevenção & controle , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Adulto Jovem
2.
J Biomed Inform ; 96: 103239, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31238109

RESUMO

Systematic application of observational data to the understanding of impacts of cancer treatments requires detailed information models allowing meaningful comparisons between treatment regimens. Unfortunately, details of systemic therapies are scarce in registries and data warehouses, primarily due to the complex nature of the protocols and a lack of standardization. Since 2011, we have been creating a curated and semi-structured website of chemotherapy regimens, HemOnc.org. In coordination with the Observational Health Data Sciences and Informatics (OHDSI) Oncology Subgroup, we have transformed a substantial subset of this content into the OMOP common data model, with bindings to multiple external vocabularies, e.g., RxNorm and the National Cancer Institute Thesaurus. Currently, there are >73,000 concepts and >177,000 relationships in the full vocabulary. Content related to the definition and composition of chemotherapy regimens has been released within the ATHENA tool (athena.ohdsi.org) for widespread utilization by the OHDSI membership. Here, we describe the rationale, data model, and initial contents of the HemOnc vocabulary along with several use cases for which it may be valuable.

3.
J Med Internet Res ; 21(3): e13249, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30912749

RESUMO

BACKGROUND: Clinical sequencing data should be shared in order to achieve the sufficient scale and diversity required to provide strong evidence for improving patient care. A distributed research network allows researchers to share this evidence rather than the patient-level data across centers, thereby avoiding privacy issues. The Observational Medical Outcomes Partnership (OMOP) common data model (CDM) used in distributed research networks has low coverage of sequencing data and does not reflect the latest trends of precision medicine. OBJECTIVE: The aim of this study was to develop and evaluate the feasibility of a genomic CDM (G-CDM), as an extension of the OMOP-CDM, for application of genomic data in clinical practice. METHODS: Existing genomic data models and sequencing reports were reviewed to extend the OMOP-CDM to cover genomic data. The Human Genome Organisation Gene Nomenclature Committee and Human Genome Variation Society nomenclature were adopted to standardize the terminology in the model. Sequencing data of 114 and 1060 patients with lung cancer were obtained from the Ajou University School of Medicine database of Ajou University Hospital and The Cancer Genome Atlas, respectively, which were transformed to a format appropriate for the G-CDM. The data were compared with respect to gene name, variant type, and actionable mutations. RESULTS: The G-CDM was extended into four tables linked to tables of the OMOP-CDM. Upon comparison with The Cancer Genome Atlas data, a clinically actionable mutation, p.Leu858Arg, in the EGFR gene was 6.64 times more frequent in the Ajou University School of Medicine database, while the p.Gly12Xaa mutation in the KRAS gene was 2.02 times more frequent in The Cancer Genome Atlas dataset. The data-exploring tool GeneProfiler was further developed to conduct descriptive analyses automatically using the G-CDM, which provides the proportions of genes, variant types, and actionable mutations. GeneProfiler also allows for querying the specific gene name and Human Genome Variation Society nomenclature to calculate the proportion of patients with a given mutation. CONCLUSIONS: We developed the G-CDM for effective integration of genomic data with standardized clinical data, allowing for data sharing across institutes. The feasibility of the G-CDM was validated by assessing the differences in data characteristics between two different genomic databases through the proposed data-exploring tool GeneProfiler. The G-CDM may facilitate analyses of interoperating clinical and genomic datasets across multiple institutions, minimizing privacy issues and enabling researchers to better understand the characteristics of patients and promote personalized medicine in clinical practice.

4.
Stress ; 21(2): 169-178, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29307250

RESUMO

Psychosocial stress is linked to the etiology of several neuropsychiatric disorders, including Major Depressive Disorder and Post-Traumatic-Stress-Disorder. Adolescence is a critical neurobehavioral developmental period wherein the maturing nervous system is sensitive to stress-related psychosocial events. The effects of social defeat stress, an animal model of psychosocial stress, on adolescent neurobehavioral phenomena are not well explored. Using the standard Resident-Intruder-Paradigm (RIP), adolescent Long-Evans (LE, residents, n = 100) and Sprague-Dawley (SD, intruders, n = 100) rats interacted for five days to invoke chronic social stress. Tests of depressive behavior (forced-swim-test (FST)), fear conditioning, and long-term synaptic plasticity are affected in various adult rodent chronic stress models, thus we hypothesized that these phenomena would be similarly affected in adolescent rats. Serendipitously, we observed the Intruders became the dominant rats and the Residents were the defeated/submissive rats. This robust and reliable role-reversal resulted in defeated LE-Residents showing a depressive-like state (increased time spent immobile in the FST), enhanced fear conditioning in both hippocampal-dependent and hippocampal-independent fear paradigms and altered hippocampal long-term synaptic plasticity, measured electrophysiologically in vitro in hippocampal slices. Importantly, SD-Intruders, SD and LE controls did not significantly differ from each other in any of these assessments. This reverse-Resident-Intruder-Paradigm (rRIP) represents a novel animal model to study the effects of stress on adolescent neurobehavioral phenomenon.


Assuntos
Depressão/fisiopatologia , Dominação-Subordinação , Plasticidade Neuronal/fisiologia , Estresse Psicológico/fisiopatologia , Animais , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Medo , Hipocampo/fisiopatologia , Masculino , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley
5.
JAMA Netw Open ; 1(4): e181755, 2018 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-30646124

RESUMO

Importance: Consensus around an efficient second-line treatment option for type 2 diabetes (T2D) remains ambiguous. The availability of electronic medical records and insurance claims data, which capture routine medical practice, accessed via the Observational Health Data Sciences and Informatics network presents an opportunity to generate evidence for the effectiveness of second-line treatments. Objective: To identify which drug classes among sulfonylureas, dipeptidyl peptidase 4 (DPP-4) inhibitors, and thiazolidinediones are associated with reduced hemoglobin A1c (HbA1c) levels and lower risk of myocardial infarction, kidney disorders, and eye disorders in patients with T2D treated with metformin as a first-line therapy. Design, Setting, and Participants: Three retrospective, propensity-matched, new-user cohort studies with replication across 8 sites were performed from 1975 to 2017. Medical data of 246 558 805 patients from multiple countries from the Observational Health Data Sciences and Informatics (OHDSI) initiative were included and medical data sets were transformed into a unified common data model, with analysis done using open-source analytical tools. Participants included patients with T2D receiving metformin with at least 1 prior HbA1c laboratory test who were then prescribed either sulfonylureas, DPP-4 inhibitors, or thiazolidinediones. Data analysis was conducted from 2015 to 2018. Exposures: Treatment with sulfonylureas, DPP-4 inhibitors, or thiazolidinediones starting at least 90 days after the initial prescription of metformin. Main Outcomes and Measures: The primary outcome is the first observation of the reduction of HbA1c level to 7% of total hemoglobin or less after prescription of a second-line drug. Secondary outcomes are myocardial infarction, kidney disorder, and eye disorder after prescription of a second-line drug. Results: A total of 246 558 805 patients (126 977 785 women [51.5%]) were analyzed. Effectiveness of sulfonylureas, DPP-4 inhibitors, and thiazolidinediones prescribed after metformin to lower HbA1c level to 7% or less of total hemoglobin remained indistinguishable in patients with T2D. Patients treated with sulfonylureas compared with DPP-4 inhibitors had a small increased consensus hazard ratio of myocardial infarction (1.12; 95% CI, 1.02-1.24) and eye disorders (1.15; 95% CI, 1.11-1.19) in the meta-analysis. Hazard of observing kidney disorders after treatment with sulfonylureas, DPP-4 inhibitors, or thiazolidinediones was equally likely. Conclusions and Relevance: The examined drug classes did not differ in lowering HbA1c and in hazards of kidney disorders in patients with T2D treated with metformin as a first-line therapy. Sulfonylureas had a small, higher observed hazard of myocardial infarction and eye disorders compared with DPP-4 inhibitors in the meta-analysis. The OHDSI collaborative network can be used to conduct a large international study examining the effectiveness of second-line treatment choices made in clinical management of T2D.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hemoglobina A Glicada/análise , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Compostos de Sulfonilureia/uso terapêutico , Tiazolidinedionas/uso terapêutico , Estudos de Coortes , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Feminino , Humanos , Masculino , Compostos de Sulfonilureia/efeitos adversos , Tiazolidinedionas/efeitos adversos
6.
Pharmacoepidemiol Drug Saf ; 25(9): 973-81, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27418432

RESUMO

BACKGROUND: We reviewed the results of the Observational Medical Outcomes Research Partnership (OMOP) 2010 Experiment in hopes of finding examples where apparently well-designed drug studies repeatedly produce anomalous findings. OMOP had applied thousands of designs and design parameters to 53 drug-outcome pairs across 10 electronic data resources. Our intent was to use this repository to elucidate some sources of error in observational studies. METHOD: From the 2010 OMOP Experiment, we sought drug-outcome-method combinations (DOMCs) that met consensus design criteria, yet repeatedly produced results contrary to expectation. We set aside DOMCs for which we could not agree on the suitability of the designs, then selected for an in-depth scrutiny one drug-outcome pair analyzed by a seemingly plausible methodological approach, whose results consistently disagreed with the a priori expectation. RESULTS: The OMOP "all-by-all" assessment of possible DOMCs yielded many combinations that would not be chosen by researchers as actual study options. Among those that passed a first level of scrutiny, two of seven drug-outcome pairs for which there were plausible research designs had anomalous results. The use of benzodiazepines was unexpectedly associated with acute renal failure and upper gastrointestinal bleeding. We chose the latter as an example for in-depth study. The factitious appearance of a bleeding risk may have been partly driven by an excess of procedures on the first day of treatment. A risk window definition that excluded the first day largely removed the spurious association. CONCLUSION: One cause of reproducible "error" may be repeated failure to tie design choices closely enough to the research question at hand. Copyright © 2016 John Wiley & Sons, Ltd.


Assuntos
Estudos Observacionais como Assunto/métodos , Vigilância de Produtos Comercializados/métodos , Projetos de Pesquisa , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Humanos , Estudos Observacionais como Assunto/normas , Reprodutibilidade dos Testes
7.
Proc Natl Acad Sci U S A ; 113(27): 7329-36, 2016 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-27274072

RESUMO

Observational research promises to complement experimental research by providing large, diverse populations that would be infeasible for an experiment. Observational research can test its own clinical hypotheses, and observational studies also can contribute to the design of experiments and inform the generalizability of experimental research. Understanding the diversity of populations and the variance in care is one component. In this study, the Observational Health Data Sciences and Informatics (OHDSI) collaboration created an international data network with 11 data sources from four countries, including electronic health records and administrative claims data on 250 million patients. All data were mapped to common data standards, patient privacy was maintained by using a distributed model, and results were aggregated centrally. Treatment pathways were elucidated for type 2 diabetes mellitus, hypertension, and depression. The pathways revealed that the world is moving toward more consistent therapy over time across diseases and across locations, but significant heterogeneity remains among sources, pointing to challenges in generalizing clinical trial results. Diabetes favored a single first-line medication, metformin, to a much greater extent than hypertension or depression. About 10% of diabetes and depression patients and almost 25% of hypertension patients followed a treatment pathway that was unique within the cohort. Aside from factors such as sample size and underlying population (academic medical center versus general population), electronic health records data and administrative claims data revealed similar results. Large-scale international observational research is feasible.


Assuntos
Padrões de Prática Médica/estatística & dados numéricos , Antidepressivos/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Bases de Dados Factuais , Depressão/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Registros Eletrônicos de Saúde , Humanos , Hipertensão/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Internacionalidade , Informática Médica
8.
Physiol Behav ; 161: 104-115, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27083122

RESUMO

Rats avoid intake of a taste cue when paired with a drug of abuse or with the illness-inducing agent, lithium chloride (LiCl). Although progress has been made, it is difficult to compare the suppressive effects of abused agents and LiCl on intake of a gustatory conditioned stimulus (CS) because of the cross-laboratory use of different CSs, different unconditioned stimuli (USs), and different doses of the drugs, different conditioning regimens, and different restriction states. Here we have attempted to unify these variables by comparing the suppressive effects of a range of doses of morphine, cocaine, and LiCl on intake of a saccharin CS using a common regimen in non-restricted, food restricted, or water restricted male Sprague-Dawley rats. The results showed that, while the putatively aversive agent, LiCl, was effective in suppressing intake of the taste cue across nearly all doses, regardless of restriction state, the suppressive effects of both morphine and cocaine were greatly reduced when evaluated in either food or water restricted rats. Greater sensitivity to drug was revealed, at very low doses, when testing occurred in the absence of need (i.e., when the rats were non-restricted). Together, these results provide the first uniform and comprehensive analysis of the suppressive effects of morphine, cocaine, and LiCl as a function of dose and restriction state. In the present case, the suppressive effects of morphine and cocaine are found to differ from those of LiCl and, in some respects, from one another as well.


Assuntos
Antimaníacos/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Cocaína/farmacologia , Cloreto de Lítio/farmacologia , Morfina/farmacologia , Entorpecentes/farmacologia , Sacarina/administração & dosagem , Vasoconstritores/farmacologia , Animais , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Privação de Alimentos , Preferências Alimentares , Masculino , Ratos , Ratos Sprague-Dawley , Privação de Água
9.
Stud Health Technol Inform ; 216: 574-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26262116

RESUMO

The vision of creating accessible, reliable clinical evidence by accessing the clincial experience of hundreds of millions of patients across the globe is a reality. Observational Health Data Sciences and Informatics (OHDSI) has built on learnings from the Observational Medical Outcomes Partnership to turn methods research and insights into a suite of applications and exploration tools that move the field closer to the ultimate goal of generating evidence about all aspects of healthcare to serve the needs of patients, clinicians and all other decision-makers around the world.


Assuntos
Bases de Dados Factuais , Pesquisa sobre Serviços de Saúde/organização & administração , Informática Médica/organização & administração , Modelos Organizacionais , Estudos Observacionais como Assunto , Internacionalidade
11.
J Neurophysiol ; 112(2): 263-75, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24760782

RESUMO

GluA2-lacking, calcium-permeable α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPARs) have unique properties, but their presence at excitatory synapses in pyramidal cells is controversial. We have tested certain predictions of the model that such receptors are present in CA1 cells and show here that the polyamine spermine, but not philanthotoxin, causes use-dependent inhibition of synaptically evoked excitatory responses in stratum radiatum, but not s. oriens, in cultured and acute hippocampal slices. Stimulation of single dendritic spines by photolytic release of caged glutamate induced an N-methyl-d-aspartate receptor-independent, use- and spermine-sensitive calcium influx only at apical spines in cultured slices. Bath application of glutamate also triggered a spermine-sensitive influx of cobalt into CA1 cell dendrites in s. radiatum. Responses of single apical, but not basal, spines to photostimulation displayed prominent paired-pulse facilitation (PPF) consistent with use-dependent relief of cytoplasmic polyamine block. Responses at apical dendrites were diminished, and PPF was increased, by spermine. Intracellular application of pep2m, which inhibits recycling of GluA2-containing AMPARs, reduced apical spine responses and increased PPF. We conclude that some calcium-permeable, polyamine-sensitive AMPARs, perhaps lacking GluA2 subunits, are present at synapses on apical dendrites of CA1 pyramidal cells, which may allow distinct forms of synaptic plasticity and computation at different sets of excitatory inputs.


Assuntos
Região CA1 Hipocampal/metabolismo , Cálcio/metabolismo , Espinhas Dendríticas/metabolismo , Células Piramidais/metabolismo , Receptores de AMPA/metabolismo , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/fisiologia , Cobalto/farmacologia , Espinhas Dendríticas/fisiologia , Potenciais Pós-Sinápticos Excitadores , Ácido Glutâmico/farmacologia , Masculino , Poliaminas/farmacologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Ratos , Ratos Sprague-Dawley , Espermina/farmacologia , Sinapses/metabolismo , Sinapses/fisiologia
12.
Drug Saf ; 36 Suppl 1: S49-58, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24166223

RESUMO

OBJECTIVE: The objective of this study is to present a data quality assurance program for disparate data sources loaded into a Common Data Model, highlight data quality issues identified and resolutions implemented. BACKGROUND: The Observational Medical Outcomes Partnership is conducting methodological research to develop a system to monitor drug safety. Standard processes and tools are needed to ensure continuous data quality across a network of disparate databases, and to ensure that procedures used to extract-transform-load (ETL) processes maintain data integrity. Currently, there is no consensus or standard approach to evaluate the quality of the source data, or ETL procedures. METHODS: We propose a framework for a comprehensive process to ensure data quality throughout the steps used to process and analyze the data. The approach used to manage data anomalies includes: (1) characterization of data sources; (2) detection of data anomalies; (3) determining the cause of data anomalies; and (4) remediation. FINDINGS: Data anomalies included incomplete raw dataset: no race or year of birth recorded. Implausible data: year of birth exceeding current year, observation period end date precedes start date, suspicious data frequencies and proportions outside normal range. Examples of errors found in the ETL process were zip codes incorrectly loaded, drug quantities rounded, drug exposure length incorrectly calculated, and condition length incorrectly programmed. CONCLUSIONS: Complete and reliable observational data are difficult to obtain, data quality assurance processes need to be continuous as data is regularly updated; consequently, processes to assess data quality should be ongoing and transparent.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Processamento Eletrônico de Dados/normas , Estatística como Assunto/normas , Bases de Dados Factuais , Humanos
13.
Drug Saf ; 36 Suppl 1: S143-58, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24166231

RESUMO

BACKGROUND: Observational healthcare data offer the potential to enable identification of risks of medical products, and the medical literature is replete with analyses that aim to accomplish this objective. A number of established analytic methods dominate the literature but their operating characteristics in real-world settings remain unknown. OBJECTIVES: To compare the performance of seven methods (new user cohort, case control, self-controlled case series, self-controlled cohort, disproportionality analysis, temporal pattern discovery, and longitudinal gamma poisson shrinker) as tools for risk identification in observational healthcare data. RESEARCH DESIGN: The experiment applied each method to 399 drug-outcome scenarios (165 positive controls and 234 negative controls across 4 health outcomes of interest) in 5 real observational databases (4 administrative claims and 1 electronic health record). MEASURES: Method performance was evaluated through Area Under the receiver operator characteristics Curve (AUC), bias, mean square error, and confidence interval coverage probability. RESULTS: Multiple methods offer strong predictive accuracy, with AUC > 0.70 achievable for all outcomes and databases with more than one analytical approach. Self-controlled methods (self-controlled case series, temporal pattern discovery, self-controlled cohort) had higher predictive accuracy than cohort and case-control methods across all databases and outcomes. Methods differed in the expected value and variance of the error distribution. All methods had lower coverage probability than the expected nominal properties. CONCLUSIONS: Observational healthcare data can inform risk identification of medical product effects on acute liver injury, acute myocardial infarction, acute renal failure and gastrointestinal bleeding. However, effect estimates from all methods require calibration to address inconsistency in method operating characteristics. Further empirical evaluation is required to gauge the generalizability of these findings to other databases and outcomes.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Projetos de Pesquisa , Medição de Risco/métodos , Área Sob a Curva , Bases de Dados Factuais , Humanos
14.
Drug Saf ; 36 Suppl 1: S181-93, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24166234

RESUMO

BACKGROUND: A systematic risk identification system has the potential to test marketed drugs for important Health Outcomes of Interest or HOI. For each HOI, multiple definitions are used in the literature, and some of them are validated for certain databases. However, little is known about the effect of different definitions on the ability of methods to estimate their association with medical products. OBJECTIVES: Alternative definitions of HOI were studied for their effect on the performance of analytical methods in observational outcome studies. METHODS: A set of alternative definitions for three HOI were defined based on literature review and clinical diagnosis guidelines: acute kidney injury, acute liver injury and acute myocardial infarction. The definitions varied by the choice of diagnostic codes and the inclusion of procedure codes and lab values. They were then used to empirically study an array of analytical methods with various analytical choices in four observational healthcare databases. The methods were executed against predefined drug-HOI pairs to generate an effect estimate and standard error for each pair. These test cases included positive controls (active ingredients with evidence to suspect a positive association with the outcome) and negative controls (active ingredients with no evidence to expect an effect on the outcome). Three different performance metrics where used: (i) Area Under the Receiver Operator Characteristics (ROC) curve (AUC) as a measure of a method's ability to distinguish between positive and negative test cases, (ii) Measure of bias by estimation of distribution of observed effect estimates for the negative test pairs where the true effect can be assumed to be one (no relative risk), and (iii) Minimal Detectable Relative Risk (MDRR) as a measure of whether there is sufficient power to generate effect estimates. RESULTS: In the three outcomes studied, different definitions of outcomes show comparable ability to differentiate true from false control cases (AUC) and a similar bias estimation. However, broader definitions generating larger outcome cohorts allowed more drugs to be studied with sufficient statistical power. CONCLUSIONS: Broader definitions are preferred since they allow studying drugs with lower prevalence than the more precise or narrow definitions while showing comparable performance characteristics in differentiation of signal vs. no signal as well as effect size estimation.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Projetos de Pesquisa , Lesão Renal Aguda/induzido quimicamente , Área Sob a Curva , Viés , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Humanos , Infarto do Miocárdio/induzido quimicamente , Estudos Observacionais como Assunto
15.
Drug Saf ; 36 Suppl 1: S195-204, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24166235

RESUMO

BACKGROUND: A systematic risk identification system has the potential to study all marketed drugs. However, the rates of drug exposure and outcome occurrences in observational databases, the database size and the desired risk detection threshold determine the power and therefore limit the feasibility of the application of appropriate analytical methods. Drugs vary dramatically for these parameters because of their prevalence of indication, cost, time on the market, payer formularies, market pressures and clinical guidelines. OBJECTIVES: Evaluate (i) the feasibility of a risk identification system based on commercially available observational databases, (ii) the range of drugs that can be studied for certain outcomes, (iii) the influence of underpowered drug-outcome pairs on the performance of analytical methods estimating the strength of their association and (iv) the time required from the introduction of a new drug to accumulate sufficient data for signal detection. METHODS: As part of the Observational Medical Outcomes Partnership experiment, we used data from commercially available observational databases and calculated the minimal detectable relative risk of all pairs of marketed drugs and eight health outcomes of interest. We then studied an array of analytical methods for their ability to distinguish between pre-determined positive and negative drug-outcome test pairs. The positive controls contained active ingredients with evidence of a positive association with the outcome, and the negative controls had no such evidence. As a performance measure we used the area under the receiver operator characteristics curve (AUC). We compared the AUC of methods using all test pairs or only pairs sufficiently powered for detection of a relative risk of 1.25. Finally, we studied all drugs introduced to the market in 2003-2008 and determined the time required to achieve the same minimal detectable relative risk threshold. RESULTS: The performance of methods improved after restricting them to fully powered drug-outcome pairs. The availability of drug-outcome pairs with sufficient power to detect a relative risk of 1.25 varies enormously among outcomes. Depending on the market uptake, drugs can generate relevant signals in the first month after approval, or never reach sufficient power. CONCLUSION: The incidence of drugs and important outcomes determines sample size and method performance in estimating drug-outcome associations. Careful consideration is therefore necessary to choose databases and outcome definitions, particularly for newly introduced drugs.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Projetos de Pesquisa , Medição de Risco/métodos , Lesão Renal Aguda/induzido quimicamente , Área Sob a Curva , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Estudos de Viabilidade , Hemorragia Gastrointestinal/induzido quimicamente , Humanos , Infarto do Miocárdio/induzido quimicamente
16.
J Psychopharmacol ; 27(10): 947-55, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23926242

RESUMO

History of stress is considered a major risk factor for the development of major depression and posttraumatic stress disorder (PTSD). Elucidating the neurobiological mechanisms of Pavlovian fear conditioning may provide insight into the etiology of PTSD. In the current study, adolescent male Sprague-Dawley rats were exposed to 3 weeks of a chronic-mild-unpredictable stress (CMS) protocol. Immediately following the CMS, the animals were subjected to hippocampal-dependent (trace and contextual) and hippocampal-independent (delay) fear conditioning. CMS exposure enhanced trace freezing behavior compared to non-stress controls. This effect was not observed in contextual or delay conditioned animals. Given that the endocannabinoid system is negatively affected by CMS procedures, separate groups of stressed rats were administered the CB1 receptor agonist, ACEA (0.1 mg/kg), prior to trace fear conditioning or a memory-recall test. Regardless of administration time, ACEA significantly reduced freezing behavior in stressed animals. Furthermore, when administered during the first memory recall test, ACEA enhanced long-term extinction in both stress and non-stress groups. The results demonstrate that chronic unpredictable stress selectively enhances hippocampal-dependent episodic fear memories. Pathologies of the episodic memory and fear response may increase the susceptibility of developing PTSD. Reduction in fear responses via exogenous activation of the CB1 receptor suggests that a deficiency in the endocannabinoid system contributes to this pathology.


Assuntos
Ácidos Araquidônicos/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Medo/efeitos dos fármacos , Medo/psicologia , Receptor CB1 de Canabinoide/agonistas , Estresse Psicológico/psicologia , Fatores Etários , Animais , Extinção Psicológica/efeitos dos fármacos , Masculino , Rememoração Mental/efeitos dos fármacos , Ratos
17.
J Am Med Inform Assoc ; 19(1): 54-60, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22037893

RESUMO

OBJECTIVE: Systematic analysis of observational medical databases for active safety surveillance is hindered by the variation in data models and coding systems. Data analysts often find robust clinical data models difficult to understand and ill suited to support their analytic approaches. Further, some models do not facilitate the computations required for systematic analysis across many interventions and outcomes for large datasets. Translating the data from these idiosyncratic data models to a common data model (CDM) could facilitate both the analysts' understanding and the suitability for large-scale systematic analysis. In addition to facilitating analysis, a suitable CDM has to faithfully represent the source observational database. Before beginning to use the Observational Medical Outcomes Partnership (OMOP) CDM and a related dictionary of standardized terminologies for a study of large-scale systematic active safety surveillance, the authors validated the model's suitability for this use by example. VALIDATION BY EXAMPLE: To validate the OMOP CDM, the model was instantiated into a relational database, data from 10 different observational healthcare databases were loaded into separate instances, a comprehensive array of analytic methods that operate on the data model was created, and these methods were executed against the databases to measure performance. CONCLUSION: There was acceptable representation of the data from 10 observational databases in the OMOP CDM using the standardized terminologies selected, and a range of analytic methods was developed and executed with sufficient performance to be useful for active safety surveillance.


Assuntos
Bases de Dados Factuais , Farmacovigilância , Sistemas de Notificação de Reações Adversas a Medicamentos , Pesquisa sobre Serviços de Saúde , Humanos , Modelos Teóricos , Observação , Terminologia como Assunto
19.
Behav Brain Res ; 203(2): 264-9, 2009 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-19460405

RESUMO

Chronic unpredictable mild stress (CMS), an animal model of depression, downregulates hippocampal CB1 receptors in adult male rats. Given that endocannabinoids are implicated in modulating stress and anxiety and that women are vulnerable to stress-related disorders, we tested the effects of CMS on both female and male rats. Gonadectomized (gndx) and gonadally intact male and female rats were exposed to a three-week chronic stress protocol. Following CMS, CB1 receptor and fatty-acid-amide-hydrolase (FAAH) expression levels in the hippocampus were assessed by western blot analysis. CMS reliably produced a downregulation of CB1 receptors ( approximately 50%) in the hippocampus of both gndx and intact males. This effect was more robust in the dorsal than in the ventral hippocampus. Conversely, CMS produced an upregulation of CB1 receptors ( approximately 150%) in the hippocampus of both gndx and intact females. This upregulation was only observed in the dorsal hippocampus of female animals. CMS produced an upregulation of FAAH levels in both male and female animals. In non-stress control animals, males were observed to have higher CB1 levels than females, but no differences in FAAH were found. These findings suggest that the endocannabinoid (eCB) system is preferentially organized in male and female animals to respond differentially to chronic stress. These sex differences in the eCB system may help development of novel treatments for stress and depression that are designed specifically for women and men.


Assuntos
Hipocampo/metabolismo , Hipocampo/fisiopatologia , Receptor CB1 de Canabinoide/metabolismo , Estresse Psicológico/fisiopatologia , Amidoidrolases/metabolismo , Animais , Western Blotting , Corticosterona/sangue , Regulação para Baixo , Feminino , Hormônios Esteroides Gonadais/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Caracteres Sexuais , Estresse Psicológico/metabolismo , Regulação para Cima
20.
J Undergrad Neurosci Educ ; 7(2): A65-8, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-23493230

RESUMO

The Northeast Under/Graduate Research Organization for Neuroscience (NEURON) was established 12 years ago in order to foster the training, education, and research of both undergraduate and graduate neuroscience students. NEURON hosts two annual conferences (Boston in the fall; New York City in the spring) to promote and support neuroscience training, education, and research. For 12 years, the organization has promoted neuroscience by exposing neuroscience trainees to research and educational perspectives (Edinger et al., 2004, 2005; Frye and Edinger, 2004; Goyette et al., 2008; Rhodes et al., 2006, 2007, 2008). Conferences are supported by an NIH R13 grant, and serve as a valuable experience for both students and mentors with a passion for neuroscience. This paper describes the proceedings of the fall 2007 meeting at Northeastern University.

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