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BACKGROUND: Most totally blind people have non-24-hour sleep-wake disorder (non-24), a rare circadian rhythm disorder caused by an inability of light to reset their circadian pacemaker. In two consecutive placebo-controlled trials (SET and RESET), we assessed safety and efficacy (in terms of circadian entrainment and maintenance) of once-daily tasimelteon, a novel dual-melatonin receptor agonist. METHODS: We undertook the placebo-controlled, randomised, double-masked trials in 27 US and six German clinical research centres and sleep centres. We screened totally blind adults (18-75 years of age), who were eligible for the randomisation phase of SET if they had a non-24-hour circadian period (τ) of 24·25 h or longer (95% CI greater than 24·0 and up to 24·9 h), as calculated from measurements of urinary 6-sulphatoxymelatonin rhythms. For SET, we used block randomisation to assign patients (1:1) to receive tasimelteon (20 mg) or placebo every 24 h at a fixed clock time 1 h before target bedtime for 26 weeks. Patients who entered the open-label group receiving tasimelteon in SET or who did not meet the SET inclusion criteria but did meet the RESET inclusion criteria were screened for RESET. A subset of the patients who entered the open-label group before the RESET study and who had eligible τ values were screened for RESET after completing the open-label treatment. In RESET, we withdrew tasimelteon in a randomised manner (1:1) in patients who responded (ie, entrained) after a tasimelteon run-in period. Entrainment was defined as having τ of 24·1 h or less and a 95% CI that included 24·0 h. In SET, the primary endpoint was the proportion of entrained patients, assessed in the intention-to-treat population. The planned step-down primary endpoint assessed the proportion of patients who had a clinical response (entrainment at month 1 or month 7 plus clinical improvement, measured by the Non-24 Clinical Response Scale). In RESET, the primary endpoint was the proportion of non-entrained patients, assessed in the intention-to-treat population. Safety assessments included adverse events and clinical laboratory measures, assessed in all treated patients. These trials are registered with ClinicalTrials.gov, numbers NCT01163032 and NCT01430754. FINDINGS: Between Aug 25, 2010, and July 5, 2012, we screened 391 totally blind patients for SET, of whom 84 (22%) were assigned to receive tasimelteon (n=42) or placebo (n=42). Two patients in the tasimelteon group and four in the placebo group discontinued the study before τ was measured, due to adverse events, withdrawal of consent, and a protocol deviation. Circadian entrainment occurred in eight (20%) of 40 patients in the tasimelteon group compared with one (3%) of 38 patients in the placebo group at month 1 (difference 17%, 95% CI 3·2-31·6; p=0·0171). Nine (24%) of 38 patients showed a clinical response, compared with none of 34 in the placebo group (difference 24%, 95% CI 8·4-39·0; p=0·0028). Between Sept 15, 2011, and Oct 4, 2012, we screened 58 patients for eligibility in RESET, 48 (83%) of whom had τ assessed and entered the open-label tasimelteon run-in phase. 24 (50%) patients entrained, and 20 (34%) were enrolled in the randomisation phase. Two (20%) of ten patients who were withdrawn to placebo remained entrained compared with nine (90%) of ten who continued to receive tasimelteon (difference 70%, 95% CI 26·4-100·0; p=0·0026). No deaths were reported in either study, and discontinuation rates due to adverse events were comparable between the tasimelteon (3 [6%] of 52 patients) and placebo (2 [4%] of 52 patients) treatment courses. The most common side-effects associated with tasimelteon in SET were headache (7 [17%] of 42 patients given tasimelteon vs 3 [7%] of 42 patients given placebo), elevated liver enzymes (4 [10%] vs 2 [5%]), nightmares or abnormal dreams (4 [10%] vs none), upper respiratory tract infection (3 [7%] vs none], and urinary tract infections (3 [7%] vs 1 [2%]). INTERPRETATION: Once-daily tasimelteon can entrain totally blind people with non-24; however, continued tasimelteon treatment is necessary to maintain these improvements. FUNDING: Vanda Pharmaceuticals.
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Benzofuranos/uso terapéutico , Ceguera/complicaciones , Ciclopropanos/uso terapéutico , Receptores de Melatonina/agonistas , Trastornos del Sueño del Ritmo Circadiano/tratamiento farmacológico , Ritmo Circadiano/efectos de los fármacos , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos del Sueño del Ritmo Circadiano/etiología , Resultado del TratamientoRESUMEN
BACKGROUND: There is a large amount of gene expression data that exists in the public domain. This data has been generated under a variety of experimental conditions. Unfortunately, these experimental variations have generally prevented researchers from accurately comparing and combining this wealth of data, which still hides many novel insights. RESULTS: In this paper we present a new method, which we refer to as indirect two-sided relative ranking, for comparing gene expression profiles that is robust to variations in experimental conditions. This method extends the current best approach, which is based on comparing the correlations of the up and down regulated genes, by introducing a comparison based on the correlations in rankings across the entire database. Because our method is robust to experimental variations, it allows a greater variety of gene expression data to be combined, which, as we show, leads to richer scientific discoveries. CONCLUSIONS: We demonstrate the benefit of our proposed indirect method on several datasets. We first evaluate the ability of the indirect method to retrieve compounds with similar therapeutic effects across known experimental barriers, namely vehicle and batch effects, on two independent datasets (one private and one public). We show that our indirect method is able to significantly improve upon the previous state-of-the-art method with a substantial improvement in recall at rank 10 of 97.03% and 49.44%, on each dataset, respectively. Next, we demonstrate that our indirect method results in improved accuracy for classification in several additional datasets. These datasets demonstrate the use of our indirect method for classifying cancer subtypes, predicting drug sensitivity/resistance, and classifying (related) cell types. Even in the absence of a known (i.e., labeled) experimental barrier, the improvement of the indirect method in each of these datasets is statistically significant.
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Biología Computacional/métodos , Perfilación de la Expresión Génica/métodos , Expresión Génica , Bases de Datos Genéticas , Reconocimiento de Normas Patrones Automatizadas/métodosRESUMEN
For decades, the dopamine hypothesis has gained the most attention in an attempt to explain the origin and the symptoms of schizophrenia. While this hypothesis offers an explanation for the relationship between psychotic symptoms and dopamine kinetics, it does not provide a direct explanation of the etiology of schizophrenia which remains poorly understood. Consequently, current antipsychotics that target neurotransmitter receptors, have limited and inconsistent efficacy. To gain insights into the mechanism of action of these drugs, we studied the expression profile of 12,490 human genes in a cell line treated with 18 antipsychotics, and compared it to that of a library of 448 other compounds used in a variety of disorders. Analysis reveals a common effect of antipsychotics on the biosynthesis and regulation of fatty acids and cholesterol, which is discussed in the context of a lipid hypothesis where alterations in lipid homeostasis might underlie the pathogenesis of schizophrenia. This finding may help research aimed at the development of novel treatments for this devastating disease.
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Antipsicóticos/farmacología , Colesterol/metabolismo , Células Epiteliales/efectos de los fármacos , Ácidos Grasos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Línea Celular Transformada , Perfilación de la Expresión Génica/métodos , Regulación de la Expresión Génica/fisiología , Humanos , Análisis por Micromatrices/métodos , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Retina/citología , Estadísticas no ParamétricasRESUMEN
Databases often contain uncertain and imprecise references to real-world entities. Entity resolution, the process of reconciling multiple references to underlying real-world entities, is an important data cleaning process required before accurate visualization or analysis of the data is possible. In many cases, in addition to noisy data describing entities, there is data describing the relationships among the entities. This relational data is important during the entity resolution process; it is useful both for the algorithms which determine likely database references to be resolved and for visual analytic tools which support the entity resolution process. In this paper, we introduce a novel user interface, D-Dupe, for interactive entity resolution in relational data. D-Dupe effectively combines relational entity resolution algorithms with a novel network visualization that enables users to make use of an entity's relational context for making resolution decisions. Since resolution decisions often are interdependent, D-Dupe facilitates understanding this complex process through animations which highlight combined inferences and a history mechanism which allows users to inspect chains of resolution decisions. An empirical study with 12 users confirmed the benefits of the relational context visualization on the performance of entity resolution tasks in relational data in terms of time as well as users' confidence and satisfaction.
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Algoritmos , Gráficos por Computador , Sistemas de Administración de Bases de Datos , Bases de Datos Factuales , Interpretación de Imagen Asistida por Computador/métodos , Interfaz Usuario-Computador , Almacenamiento y Recuperación de la InformaciónRESUMEN
STUDY OBJECTIVES: The absence of a screening questionnaire for delayed sleep phase disorder (DSPD) remains a barrier to its detection and subsequent clinical evaluation. We developed a questionnaire to screen for DSPD risk and assessed its impact on self-reported absenteeism and functioning in work/school, social, and family life. DESIGN: Cross-sectional, with 13,844 individuals responding to a survey through an Internet survey provider, from which 1315 completed surveys were obtained from eligible participants. PARTICIPANTS: A total of 1315 individuals who self-identified as evening type (n=979) or as non-evening type (n=356). MEASUREMENTS AND RESULTS: A total of 295 participants were at high risk for DSPD, which is 5.1% of the total eligible survey respondents and 22.4% of our final sample with completed surveys. Compared to those who were not at high risk for DSPD, those who were at high risk were more likely to report frequent absenteeism, frequent loss of productivity, disruption to work or school activities, disruption to social life or leisure activities, and disruption to family life or home responsibilities. Difficulty with daytime sleepiness was more common in those at high risk for DSPD than those who were not. Increased sleep deficit on nights before school or work was also associated with more frequent difficulties with daytime sleepiness; 15.4% of those with no sleep deficit reported always or usually having difficulties with daytime sleepiness compared to 55.7% of those with a sleep deficit of 3hours or more. CONCLUSIONS: DSPD risk is associated with increased absenteeism and impaired functioning in work/school, social, and family life.
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Gene expression microarrays are commonly used to detect the biological signature of a disease or to gain a better understanding of the underlying mechanism of how a group of drugs treat a specific disease. The outcome of such experiments, e.g. the signature, is a list of differentially expressed genes. Reproducibility across independent experiments remains a challenge. We are interested in creating a method that can detect the shared signature of a group of expression profiles, e.g. a group of samples from individuals with the same disease or a group of drugs that treat the same therapeutic indication. We have developed a novel Weighted Influence-Rank of Ranks (WIMRR) method, and we demonstrate its ability to produce both meaningful and reproducible group signatures.
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Perfilación de la Expresión Génica/estadística & datos numéricos , Corticoesteroides/farmacología , Antidepresivos/farmacología , Antipsicóticos/farmacología , Biología Computacional , Minería de Datos/estadística & datos numéricos , Descubrimiento de Drogas/estadística & datos numéricos , Expresión Génica/efectos de los fármacos , Antagonistas de los Receptores Histamínicos/farmacología , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos/estadística & datos numéricos , Proyectos PilotoRESUMEN
OBJECTIVE: To demonstrate how several polymorphisms previously associated with the efficacy of the novel antipsychotic iloperidone could be used together to predict clinical response and provide practical information for individualized treatment. METHOD: This inpatient randomized, double-blind, placebo- and ziprasidone-controlled, 28-day study of the efficacy of iloperidone was conducted from November 2005 to September 2006. Likelihood ratios, predicted probabilities of response, and number needed to treat were calculated for patients with schizophrenia (DSM-IV criteria) using 6 genetic markers of iloperidone response as measured by change in the Positive and Negative Syndrome Scale-Total (PANSS-T) score. Data analysis was performed on 409 patients of various ethnic origins. RESULTS: The 6-marker genotype combinations defined 4 groups of patients with distinct probabilities of response. More than 75% of iloperidone-treated patients in the group with the optimal genotype combinations showed a 20% or greater improvement, compared with 37% for patients with other genotypes. These patients had a significant response by the first week of treatment, which was earlier than for patients with other genotype combinations. The odds of responding to iloperidone treatment with at least 20% improvement ranged from 2.4 to 3.6 for patients with 1 of the 6 favorable single-marker genotypes. The odds increased to 9.5 or greater for patients with the most favorable 6-marker combinations. The difference in PANSS-T score improvement observed between the genotype groups was also seen for the positive, negative, and general psychopathology PANSS subscales. The relationship between treatment efficacy and genotype combinations was not observed for patients treated with ziprasidone. CONCLUSION: These results illustrate the combined use of genetic markers to predict enhanced response to iloperidone and support the application of pharmacogenetics to differentiate medication options and improve individualized treatments for schizophrenia. TRIAL REGISTRATION: (ClinicalTrials.gov) Identifier: NCT00254202.