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We focus on the Fisher information matrix used for design evaluation and optimization in nonlinear mixed effects multiple response models. We evaluate the appropriateness of its expression computed by linearization as proposed for a single response model. Using a pharmacokinetic–pharmacodynamic (PKPD) example, we first compare the computation of the Fisher information matrix with approximation to one derived from the observed matrix on a large simulation using the stochastic approximation expectation–maximization algorithm (SAEM). The expression of the Fisher information matrix for multiple responses is also evaluated by comparison with the empirical information obtained through a replicated simulation study using the first‐order linearization estimation methods implemented in the NONMEM software (first‐order (FO), first‐order conditional estimate (FOCE)) and the SAEM algorithm in the MONOLIX software. The predicted errors given by the approximated information matrix are close to those given by the information matrix obtained without linearization using SAEM and to the empirical ones obtained with FOCE and SAEM. The simulation study also illustrates the accuracy of both FOCE and SAEM estimation algorithms when jointly modelling multiple responses and the major limitations of the FO method. This study highlights the appropriateness of the approximated Fisher information matrix for multiple responses, which is implemented in PFIM 3.0, an extension of the R function PFIM dedicated to design evaluation and optimization. It also emphasizes the use of this computing tool for designing population multiple response studies, as for instance in PKPD studies or in PK studies including the modelling of the PK of a drug and its active metabolite. Copyright © 2009 John Wiley & Sons, Ltd. 相似文献
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Ligue nationale contre le cancer rue Corvisart F- Paris France Site: www.ligue-cancer.net 《Oncologie》2006,8(3):298-299
Une équipe labellisée par la Ligue vient de démasquer une cellule aux propriétés extraordinaires: elle se faufile auprès des
tumeurs et les détruit en un temps record. Une première mondiale.
*Article publié dans le magazine Vivre n˚ 329 écrit par la journaliste S. Delage/Sequoia ETC. Pour vous abonner, téléphoner
au 0 810 111 101 (prix d’un appel local) 相似文献
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Patrick Manckoundia France Mourey Pierre Pfitzenmeyer Jacques Van Hoecke Dominic Pérennou 《Clinical neurophysiology》2007,118(4):786-793
OBJECTIVE: We hypothesised that backward disequilibrium (BD), defined by a posterior position of the centre of mass with respect to the base of support, could be caused by a backward tilt in the perception of verticality. METHODS: The relationship between BD, the perception of verticality, and the history of falls in 25 subjects aged 84.5+/-7.4 years was analysed. An original ordinal scale, the BD scale (BDS), was used to quantify BD. Postural (PV) and haptic verticals (HV) were measured in sagittal plane. RESULTS: BDS scores closely correlated with the number of falls (r = 0.81, p =10(-5)). The more the PV was tilted backward, the greater the BDS scores (r = -0.95, p<10(-6)), with a huge backward tilt of about 15 degrees in 4 subjects with severe BD. In these subjects, the tilt in perception of verticality was transmodal since a severe backward HV tilt was also found. CONCLUSIONS: This transmodality suggested high-order cognitive disruption in the construction of the subjective vertical used in postural control by subjects showing BD, which confirmed our hypothesis. SIGNIFICANCE: This study clearly shows that perception and action with respect to gravity are closely related and brings a new insight about fall mechanisms in the elderly. 相似文献
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Magali Louis Anne France Dekairelle Jean-Luc Gala 《Clinical chemistry and laboratory medicine》2004,42(12):1364-1369
Risk factors for cardiovascular diseases and venous thromboembolism involve both acquired and hereditary conditions. Among the latter, mutations in genes coding for coagulation factors (factor V Leiden [Arg506Gly], G20210A in the 3'-untranslated region of factor II ) and variant C677T of the methylenetetrahydrofolate reductase (MTHFR ) are often involved and co-inherited. These three factors were genotyped simultaneously in the same 96-well plate, using a real-time polymerase chain reaction (PCR) Taqman assay and minor groove binding DNA oligonucleotides (MGB probes). While primers and MGB probes matched their corresponding single nucleotide polymorphism (SNP), the real-time MGB program was identical for each target gene. Homozygous wild-type (WT; -/-), heterozygous (+/-) or homozygous (+/+) variants (n = 362) were selected for factor V (n = 115, with -/-, 40; +/-, 40; +/+, 35), factor II (n = 122, with -/-, 60; +/-, 60; +/+, 2), and MTHFR (n = 120, with -/-, 40; +/-, 40; +/+, 40), according to the results of conventional PCR-restriction fragment length polymorphism (PCR-RFLP), but the allelic discrimination was performed blind. Results of the real-time MGB and PCR-RFLP assays were identical. This new assay was easy and fast with high throughput, without risk of molecular carryover, and cost-effective for laboratories utilizing the Taqman or related fluorescence reading methods. These advantages make it particularly suitable for large-scale combined genotyping of several polymorphisms in the routine setting. 相似文献
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Radiographic assessment of instability of the knee due to rupture of the anterior cruciate ligament. A quadriceps-contraction technique 总被引:2,自引:0,他引:2
J L Franklin T D Rosenberg L E Paulos E P France 《The Journal of bone and joint surgery. American volume》1991,73(3):365-372
We compared the results of a radiographic technique for the measurement of instability of the knee with those obtained with a KT-1000 arthrometer. The study was conducted on both knees of sixty patients who had a ruptured anterior-cruciate ligament in one knee, as well as in ten control subjects. The radiographic technique included the examination of a true lateral radiograph, made while the knee was in full extension and the quadriceps was maximally contracted, with a 66.7-newton downward force produced by a 6.8-kilogram weight suspended from the ankle. As demonstrated by both techniques, the maximum difference between the displacements of the right and left knees in the control subjects was 2.5 millimeters and the mean difference between the displacements in the two knees in the patients was 7.5 millimeters. In fourteen of the sixty knees in which the ligament was ruptured, the injury was acute. The forward translation of the medial side in these fourteen knees was compared with that in the forty-six knees in which the injury was chronic. The mean difference in the displacement of the medial side in the right and left knees was 3.5 millimeters in the fourteen patients who had an acute injury and 5.0 millimeters in the forty-six patients who had a chronic injury. Thirteen of the sixty patients had disruption of the posteromedial corner of the injured knee, and the translation of the medial side in these knees was significantly increased compared with that in the intact knees of the same patients.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
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Daniel Van Gansbeke Thierry M. Metens Celso Matos Nicole Nicaise France Gay Hubert Raeymaekers Julien Struyven 《Journal of magnetic resonance imaging : JMRI》1997,7(3):482-489
This study was devoted to tumor differentiation in liver MR T1-weighted imaging with superparamagnetic iron oxide (SPIO). Twenty-one patients with 40 liver lesions were studied at 1.5 T. Before and at least 45 minutes after SPIO administration, turbo-field-echo (TFE) T1-weighted, TFE T1 × T2*-weighted (MXT), and fat-suppressed turbo-spin-echo T2-weighted images were acquired. A quantitative analysis was performed blindly. On TFE T1-weighted images, the signal enhancement was ?33% ± 12 for the liver, ?24% ± 2 for adenomas and focal nodular hyperplasia, +60% ± 33 for the hemangiomas; metastases and cyst enhancement were not significant. After SPIO on TFE T1-weighted images, the hemangioma-to-liver signal ratio (149% ± 18) was definitely higher than the mean metastasis-to-liver signal ratio (90% ± 16). This T1-related differentiation ability lacked dramatically on TFE MXT images and, in one case, was reduced on post-SPIO TFE T1-weighted images by a long imaging delay after SPIO administration (2 hours). 相似文献