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1.
Stat Med ; 41(7): 1225-1241, 2022 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-34816472

RESUMO

For semi-competing risks data involving a non-terminal event and a terminal event we derive the asymptotic distributions of the event-specific win ratios under proportional hazards (PH) assumptions for the relevant cause-specific hazard functions of the non-terminal and terminal event, respectively. The win ratios converge to the respective hazard ratios under the PH assumptions and therefore are censoring-free, whether or not the censoring distributions in the two treatment arms are the same. With the asymptotic bivariate normal distributions of the win ratios, confidence intervals and testing procedures are obtained. Through extensive simulation studies and data analysis, we identified proper transformations of the win ratios that yield good control of the type one error rate for various testing procedures while maintaining competitive power. The confidence intervals also have good coverage probabilities. Furthermore, a test for the PH assumptions and a test of equal hazard ratios are developed. The new procedures are illustrated in the clinical trial Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function, which evaluated the effects of spironolactone in patients with heart failure and a preserved left ventricular ejection fraction.


Assuntos
Insuficiência Cardíaca , Função Ventricular Esquerda , Adulto , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Modelos de Riscos Proporcionais , Espironolactona/uso terapêutico , Volume Sistólico
2.
Artigo em Inglês | MEDLINE | ID: mdl-34898770

RESUMO

Conditional independence assumption of truncation and failure times conditioning on covariates is a fundamental and common assumption in the regression analysis of left-truncated and right-censored data. Testing for this assumption is essential to ensure the correct inference on the failure time, but this has often been overlooked in the literature. With consideration of challenges caused by left truncation and right censoring, tests for this conditional independence assumption are developed in which the generalized odds ratio derived from a Cox proportional hazards model on the failure time and the concept of Kendall's tau are combined. Except for the Cox proportional hazards model, no additional model assumptions are imposed, and the distributions of the truncation time and conditioning variables are unspecified. The asymptotic properties of the test statistic are established and an easy implementation for obtaining its distribution is developed. The performance of the proposed test has been evaluated through simulation studies and two real studies.

3.
Blood Cancer J ; 11(9): 162, 2021 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-34588432

RESUMO

Acute myeloid leukemia (AML) with rearrangement of the lysine methyltransferase 2a gene (KMT2Ar) has adverse outcomes. However, reports on the prognostic impact of various translocations causing KMT2Ar are conflicting. Less is known about associated mutations and their prognostic impact. In a retrospective analysis, we identified 172 adult patients with KMT2Ar AML and compared them to 522 age-matched patients with diploid AML. KMT2Ar AML had fewer mutations, most commonly affecting RAS and FLT3 without significant impact on prognosis, except for patients with ≥2 mutations with lower overall survival (OS). KMT2Ar AML had worse outcomes compared with diploid AML when newly diagnosed and at relapse, especially following second salvage (median OS of 2.4 vs 4.8 months, P < 0.0001). Therapy-related KMT2Ar AML (t-AML) had worse outcomes compared with de novo KMT2Ar AML (median OS of 0.7 years vs 1.4 years, P < 0.0001). Allogeneic hematopoietic stem cell transplant (allo-HSCT) in first remission was associated with improved OS (5-year, 52 vs 14% for no allo-HSCT, P < 0.0001). In a multivariate analysis, translocation subtypes causing KMT2Ar did not predict survival, unlike age and allo-HSCT. In conclusion, KMT2Ar was associated with adverse outcomes regardless of translocation subtype. Therefore, AML risk stratification guidelines should include all KMT2Ar as adverse.


Assuntos
Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Rearranjo Gênico , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Transplante Homólogo , Adulto Jovem
4.
Stat Med ; 40(2): 287-298, 2021 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-33086432

RESUMO

In an infectious disease cohort study, individuals who have been infected with a pathogen are often recruited for follow up. The period between infection and the onset of symptomatic disease, referred to as the incubation period, is of interest because of its importance on disease surveillance and control. However, the incubation period is often difficult to ascertain due to the uncertainty associated with asymptomatic infection onset time. An additional complication is that the observed infected subjects are likely to have longer incubation periods due to the prevalent sampling. In this article, we demonstrate how to estimate the distribution of the incubation period with the uncertain infection onset, subject to left-truncation and right-censoring. We employ a family of sufficiently general parametric models, the generalized odds-rate class of regression models, for the underlying incubation period and its correlation with covariates. In simulation studies, we assess the finite sample performance of the model fitting and hazard function estimation. The proposed method is illustrated on data from the HIV/AIDS study on injection drug users admitted to a detoxification program in Badalona, Spain.


Assuntos
Síndrome de Imunodeficiência Adquirida , Estudos de Coortes , Simulação por Computador , Humanos , Projetos de Pesquisa , Espanha
5.
Cancer ; 126(15): 3579-3592, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32484926

RESUMO

BACKGROUND: Poor outcomes for patients with ovarian cancer relate to dormant, drug-resistant cancer cells that survive after primary surgery and chemotherapy. Ovarian cancer (OvCa) cells persist in poorly vascularized scars on the peritoneal surface and depend on autophagy to survive nutrient deprivation. The authors have sought drugs that target autophagic cancer cells selectively to eliminate residual disease. METHODS: By using unbiased small-interfering RNA (siRNA) screens, the authors observed that knockdown of anaplastic lymphoma kinase (ALK) reduced the survival of autophagic OvCa cells. Small-molecule ALK inhibitors were evaluated for their selective toxicity against autophagic OvCa cell lines and xenografts. Autophagy was induced by reexpression of GTP-binding protein Di-Ras3 (DIRAS3) or serum starvation and was evaluated with Western blot analysis, fluorescence imaging, and transmission electron microscopy. Signaling pathways required for crizotinib-induced apoptosis of autophagic cells were explored with flow cytometric analysis, Western blot analysis, short-hairpin RNA knockdown of autophagic proteins, and small-molecule inhibitors of STAT3 and BCL-2. RESULTS: Induction of autophagy by reexpression of DIRAS3 or serum starvation in multiple OvCa cell lines significantly reduced the 50% inhibitory concentration of crizotinib and other ALK inhibitors. In 2 human OvCa xenograft models, the DIRAS3-expressing tumors treated with crizotinib had significantly decreased tumor burden and long-term survival in 67% to 79% of mice. Crizotinib treatment of autophagic cancer cells further enhanced autophagy and induced autophagy-mediated apoptosis by decreasing phosphorylated STAT3 and BCL-2 signaling. CONCLUSIONS: Crizotinib may eliminate dormant, autophagic, drug-resistant OvCa cells that remain after conventional cytoreductive surgery and combination chemotherapy. A clinical trial of ALK inhibitors as maintenance therapy after second-look operations should be seriously considered.


Assuntos
Quinase do Linfoma Anaplásico/genética , Neoplasias Ovarianas/tratamento farmacológico , Fator de Transcrição STAT3/genética , Proteínas rho de Ligação ao GTP/genética , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Linhagem da Célula/genética , Sobrevivência Celular/genética , Crizotinibe/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Xenoenxertos , Humanos , Camundongos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Inibidores de Proteínas Quinases/farmacologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Transdução de Sinais/efeitos dos fármacos
6.
Stat Methods Med Res ; 29(4): 1243-1255, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31203741

RESUMO

We propose a penalized variable selection method for the Cox proportional hazards model with interval censored data. It conducts a penalized nonparametric maximum likelihood estimation with an adaptive lasso penalty, which can be implemented through a penalized EM algorithm. The method is proven to enjoy the desirable oracle property. We also extend the method to left truncated and interval censored data. Our simulation studies show that the method possesses the oracle property in samples of modest sizes and outperforms available existing approaches in many of the operating characteristics. An application to a dental caries data set illustrates the method's utility.


Assuntos
Cárie Dentária , Modelos de Riscos Proporcionais , Algoritmos , Simulação por Computador , Humanos
7.
Cancers (Basel) ; 11(5)2019 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-31035430

RESUMO

Early detection of ovarian cancer promises to reduce mortality. While serum CA125 can detect more than 60% of patients with early stage (I-II) disease, greater sensitivity might be observed with a panel of biomarkers. Ten protein antigens and 12 autoantibody biomarkers were measured in sera from 76 patients with early stage (I-II), 44 patients with late stage (III-IV) ovarian cancer and 200 healthy participants in the normal risk ovarian cancer screening study. A four-biomarker panel (CA125, osteopontin (OPN), macrophage inhibitory factor (MIF), and anti-IL-8 autoantibodies) detected 82% of early stage cancers compared to 65% with CA125 alone. In early stage subjects the area under the receiver operating characteristic curve (AUC) for the panel (0.985) was significantly greater (p < 0.001) than the AUC for CA125 alone (0.885). Assaying an independent validation set of sera from 71 early stage ovarian cancer patients, 45 late stage patients and 131 healthy women, AUC in early stage disease was improved from 0.947 with CA125 alone to 0.974 with the four-biomarker panel (p = 0.015). Consequently, OPN, MIF and IL-8 autoantibodies can be used in combination with CA125 to distinguish ovarian cancer patients from healthy controls with high sensitivity. Osteopontin appears to be a robust biomarker that deserves further evaluation in combination with CA125.

8.
Stat Methods Med Res ; 28(9): 2754-2767, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30025500

RESUMO

We propose a semiparametric multi-state frailty model to analyze clustered event-history data subject to interval censoring. The proposed model is motivated by an attempt to study the life course of dental caries at the tooth level, taking into account the multiplicity of caries states and the intra-oral clustering of observations made at periodic time points. Of particular interest is the study of the intra-oral distribution of processes leading to carious lesions, and whether this distribution varies with gender. The model assumes, in view of the covariate profile, a proportionality of the transition intensities conditional on subject-level frailties, coupled with a linear spline approximation of the log baseline intensities. The model estimation is conducted using a penalized likelihood where the smoothing parameters are estimated as reciprocal variance components under a mixed-model representation. A Bayesian method is proposed to predict tooth-level caries transition probabilities, which can be used for tailoring tooth-level caries treatment and prevention plans. Intensive simulation studies indicate that the model fitting and prediction perform reasonably well under realistic sample sizes. The practical utility of the methods is illustrated using data from a longitudinal study on oral health among children from low-income families residing in the city of Detroit, Michigan.


Assuntos
Cárie Dentária/epidemiologia , Modelos Estatísticos , Teorema de Bayes , Criança , Análise por Conglomerados , Simulação por Computador , Feminino , Humanos , Estudos Longitudinais , Masculino , Michigan/epidemiologia , Pobreza , Fatores Sexuais
9.
J Am Assoc Lab Anim Sci ; 57(4): 401-414, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29970215

RESUMO

Preparing the skin of rodents for surgery often involves multiple applications of antiseptic agents. However, fewer applications may achieve the same antiseptic outcome. We evaluated the antimicrobial efficacy and effects on intraoperative body temperature of various surgical scrub agents, including novel waterless alcohol-based (WAB) options. Prior to ventral laparotomy, female C57BL/6 mice were treated with 0.9% saline (control); 70% ethanol; 10% povidone-iodine alternated with saline or 70% ethanol; 2% chlorhexidine digluconate alternated with saline or 70% ethanol; or 1 of 3 WAB products-commercial surgical scrub A, commercial surgical scrub B, or a common commercial hand sanitizer. Core temperatures were recorded, and aerobic culture swabs were collected from the surgical site at multiple time points. Intraoperative temperature trajectories for animals treated with scrub B, 10% povidone-iodine with saline, or hand sanitizer did not differ from saline (control). Temperature trajectories of mice treated with other scrub agents did differ significantly from saline. Bacteria were not detected at the operative site after 3 scrubs of 70% ethanol or 10% povidone-iodine alternated with ethanol, 2 scrubs of scrub A or B, 1 scrub of hand sanitizer, and both 1 and 3 scrubs of 2% chlorhexidine alternated with ethanol. Scrub B and 2% chlorhexidine-ethanol demonstrated prolonged antibacterial efficacy. Histology of corresponding haired skin sections revealed no differences in postoperative healing between groups, and no postoperative infections occurred. These results indicate that various novel WAB disinfectants, particularly scrub B (61% ethanol and 1% chlorhexidine gluconate), mitigate intraoperative temperature effects associated with several traditional agents and combinations. Furthermore, reduction of skin bacterial load without adverse effects on healing was seen with fewer than triplicate applications of most tested agents. Ultimately effective skin preparation can be achieved by using only 1 or 2 applications of scrub, thus rendering the triplicate skin-prep method unnecessary in laboratory mice.


Assuntos
Anti-Infecciosos Locais/farmacologia , Clorexidina/análogos & derivados , Etanol/farmacologia , Povidona-Iodo/farmacologia , Infecção da Ferida Cirúrgica/veterinária , Animais , Antibacterianos , Anti-Infecciosos , Compostos de Benzalcônio , Clorexidina/farmacologia , Desinfetantes , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Cuidados Pré-Operatórios , Pele , Infecção da Ferida Cirúrgica/prevenção & controle
10.
Transcription ; 9(4): 205-224, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29727262

RESUMO

The genetic code sectored via tRNA charging errors, and the code progressed toward closure and universality because of evolution of aminoacyl-tRNA synthetase (aaRS) fidelity and translational fidelity mechanisms. Class I and class II aaRS folds are identified as homologs. From sequence alignments, a structurally conserved Zn-binding domain common to class I and class II aaRS was identified. A model for the class I and class II aaRS alternate folding pathways is posited. Five mechanisms toward code closure are highlighted: 1) aaRS proofreading to remove mischarged amino acids from tRNA; 2) accurate aaRS active site specification of amino acid substrates; 3) aaRS-tRNA anticodon recognition; 4) conformational coupling proofreading of the anticodon-codon interaction; and 5) deamination of tRNA wobble adenine to inosine. In tRNA anticodons there is strong wobble sequence preference that results in a broader spectrum of contacts to synonymous mRNA codon wobble bases. Adenine is excluded from the anticodon wobble position of tRNA unless it is modified to inosine. Uracil is generally preferred to cytosine in the tRNA anticodon wobble position. Because of wobble ambiguity when tRNA reads mRNA, the maximal coding capacity of the three nucleotide code read by tRNA is 31 amino acids + stops.


Assuntos
Aminoacil-tRNA Sintetases/genética , Código Genético/genética , Aminoacil-tRNA Sintetases/metabolismo , Humanos , Modelos Moleculares
11.
Transcription ; 9(3): 137-151, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29372672

RESUMO

We advocate for a tRNA- rather than an mRNA-centric model for evolution of the genetic code. The mechanism for evolution of cloverleaf tRNA provides a root sequence for radiation of tRNAs and suggests a simplified understanding of code evolution. To analyze code sectoring, rooted tRNAomes were compared for several archaeal and one bacterial species. Rooting of tRNAome trees reveals conserved structures, indicating how the code was shaped during evolution and suggesting a model for evolution of a LUCA tRNAome tree. We propose the polyglycine hypothesis that the initial product of the genetic code may have been short chain polyglycine to stabilize protocells. In order to describe how anticodons were allotted in evolution, the sectoring-degeneracy hypothesis is proposed. Based on sectoring, a simple stepwise model is developed, in which the code sectors from a 1→4→8→∼16 letter code. At initial stages of code evolution, we posit strong positive selection for wobble base ambiguity, supporting convergence to 4-codon sectors and ∼16 letters. In a later stage, ∼5-6 letters, including stops, were added through innovating at the anticodon wobble position. In archaea and bacteria, tRNA wobble adenine is negatively selected, shrinking the maximum size of the primordial genetic code to 48 anticodons. Because 64 codons are recognized in mRNA, tRNA-mRNA coevolution requires tRNA wobble position ambiguity leading to degeneracy of the code.


Assuntos
Evolução Molecular , Código Genético , RNA de Transferência/genética , Animais , Anticódon , Archaea/química , Archaea/genética , Bactérias/química , Bactérias/genética , Sequência de Bases , Humanos , Mutagênese , Conformação de Ácido Nucleico , Peptídeos/química , Peptídeos/genética , RNA de Transferência/química
12.
Transcription ; 8(4): 205-219, 2017 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-28632998

RESUMO

Cloverleaf tRNA with a 75 nucleotide (nt) core is posited to have evolved from ligation of three 31 nt minihelices followed by symmetric internal deletions of 9 nt within ligated acceptor stems. Statistical tests strongly support the model. Although the tRNA anticodon loop and T loop are homologs, their U-turns have been treated as distinct motifs. An appropriate comparison, however, shows that intercalation of D loop G19 between T loop bases 4 and 5 causes elevation of T loop base 5 and flipping of T loop bases 6 and 7 out of the 7 nt loop. In the anticodon loop, by contrast, loop bases 3-7 stack tightly to form a stiff connection to mRNA. Furthermore, we identify ancient repeat sequences of 3 (GCG), 5 (UAGCC) and 17 nt (∼CCGGGUUCAAAACCCGG) that comprise 75 out of 75 nts of the tRNA cloverleaf core. To present a sufficiently stiff 3-nt anticodon, a 7-nt anticodon loop was necessary with a U-turn between loop positions 2 and 3. Cloverleaf tRNA, therefore, was a radical evolutionary innovation essential for the 3-nt code. Conservation of GCG and UAGCC repeat sequences indicates that cloverleaf tRNA is at the interface between a strange RNA repeat world and the first evolution of molecules that fold to assume biologic functions. We posit that cloverleaf tRNA was the molecular archetype around which translation systems evolved.


Assuntos
Código Genético , RNA de Transferência/química , RNA de Transferência/genética , Sequência de Aminoácidos , Anticódon/química , Anticódon/genética , Sequência Conservada , Modelos Moleculares , Conformação de Ácido Nucleico
13.
BMC Res Notes ; 5: 236, 2012 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-22587344

RESUMO

BACKGROUND: Mass spectrometry (MS) data are often generated from various biological or chemical experiments and there may exist outlying observations, which are extreme due to technical reasons. The determination of outlying observations is important in the analysis of replicated MS data because elaborate pre-processing is essential for successful analysis with reliable results and manual outlier detection as one of pre-processing steps is time-consuming. The heterogeneity of variability and low replication are often obstacles to successful analysis, including outlier detection. Existing approaches, which assume constant variability, can generate many false positives (outliers) and/or false negatives (non-outliers). Thus, a more powerful and accurate approach is needed to account for the heterogeneity of variability and low replication. FINDINGS: We proposed an outlier detection algorithm using projection and quantile regression in MS data from multiple experiments. The performance of the algorithm and program was demonstrated by using both simulated and real-life data. The projection approach with linear, nonlinear, or nonparametric quantile regression was appropriate in heterogeneous high-throughput data with low replication. CONCLUSION: Various quantile regression approaches combined with projection were proposed for detecting outliers. The choice among linear, nonlinear, and nonparametric regressions is dependent on the degree of heterogeneity of the data. The proposed approach was illustrated with MS data with two or more replicates.


Assuntos
Algoritmos , Espectrometria de Massas/métodos , Espectrometria de Massas/estatística & dados numéricos , Pesquisa Biomédica/métodos , Pesquisa Biomédica/estatística & dados numéricos , Reprodutibilidade dos Testes
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