Fisher information matrix for nonlinear mixed effects multiple response models: Evaluation of the appropriateness of the first order linearization using a pharmacokinetic/pharmacodynamic model

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.     

A case of recurrent Miller Fisher syndrome mimicking botulism

Abstract Miller Fisher syndrome (MFS) is a rare and usually monophasic polyradiculoneuropathy characterised by ophthalmoplegia, decreased or absent tendon reflexes, and ataxia. The objective of this study was to report a case of recurrent MFS with a clinical presentation virtually indistinguishable from botulism. The patient was a young man with two episodes of increasing external ophthalmoplegia, ptosis, and ataxia with a long asymptomatic interval in between. The second episode occurred after consumption of rotten fish and was accompanied by gastrointestinal symptoms and an anticholinergic syndrome. Very rarely, MFS can present with a recurrent course. The importance of this case of recurrent MFS lies not only in its long asymptomatic period and identical clinical presentation, but also in its instructiveness regarding the differential diagnosis of MFS, particularly life-threatening botulism.     

蛋白质中两种Strand-Loop-Strand模体的判断

目的:蛋白质的结构决定其功能,为了解蛋白质功能,需要了解蛋白质结构。随着基因测序的发展,大量蛋白质一级结构被测出,但直接从蛋白质的序列出发来预测高级结构,仍很困难,尤其是三级结构的预测。然而由超二级结构获得的结构信息可用于三级结构的预测,对蛋白质三维结构及功能预测有重大意义。方法:由一级结构出发,考虑氨基酸序列信息以及氨基酸的亲疏水性,利用Fisher判别法区分两种Strand-Loop-Strand超二级结构模体。结果:采用7交叉检验,Loop长为2～8时,最后平均结果为Q=71.8%,Q_L=68.2%,Q_H=73.4%,MCC=0.39。如Loop长度相差不大时,预测结果更好,如选取Loop长为2、3、4的序列,7交叉检验结果为Q=75.2%,Q_L=69.4%,Q_H=77.7%,MCC=0.45。结论:以氨基酸信息为特征指标,利用Fisher判别法能较好地区分两种Strand-Loop-Strand超二级结构模体。     

蛛网膜下腔出血继发癫痫发作临床分析

目的：探讨蛛网膜下腔出血（SAH）继发癫痫的临床特点。方法：回顾性分析近17年来经CT证实的134例SAH患者中18例继发性癫痫患者的临床资料,重点观察癫痫发作类型与SAH之Fisher分级间的关系。全组均采用脱水降颅压、止血、抗感染等综合治疗,对于癫痫发作2次及以上的病人同时给予抗癫痫治疗。结果：于SAH72 h内继发癫痫发作12例,于病程第4～15天继发癫痫发作6例。18例中,全身性强直-阵挛发作（强直组）10例,简单部分性运动发作（简单组）4例,复杂部分性运动发作（复杂组）4例;除强直组与简单组Fisher分级比较,差异有统计学意义（P〈0.05）外,其余组间比较差异无统计学意义（P〉0.05）。根据GOS量表评定疗效,本组优9例,良2例,中2例,死亡5例。结论：SAH继发癫痫多发生在SAH早期,且以强直-阵挛发作为多见;其发作类型与SAH出血量和出血波及大脑皮质的范围密切相关。     

芳香胺致癌活性的Fisher判别研究

目的研究芳香胺致癌活性与结构参数和／或物理化学参数的关系。方法应用中心原子和官能团方法估算芳香胺的物理化学参数,结合多环芳烃结构参数,对两批芳香胺的致癌活性进行Ｆｉｓｈｅｒ判别分析。结果判别效率与汤田浩太郎等建立的系列方程中的两个（Ⅰ、Ⅲ）相近,但不及其最优方程（Ⅱ）。结论所选的物理化学参数适用于大部分芳香胺致癌活性的ＱＳＡＲ研究,Ｆｉｓｈｅｒ判别分析取得较好结果。     

高效液相色谱系统聚类分析方法在风轮菜属药材分类中的应用

目的 :探讨高效液相色谱技术应用于风轮菜属中药的鉴定研究。方法 :利用高效液相色谱提供药材的内在成分信息 ,结合模式识别技术 ,对风轮菜属植物进行了分类及鉴定。结果 :色谱数据的系统聚类结果得到了预期效果 ,这对于研究风轮菜属药材的类别及近缘性提供了依据。结论 :本方法具有简便、快捷、重现性好等优点。     

The impact of baseline covariates on the efficiency of statistical analyses of crossover designs

We investigate the impact of baseline covariates on the efficiency of statistical analyses of crossover designs. For practical considerations, we contemplate two different baseline methods: study baselines and period‐dependent baselines. For each baseline method, we establish analytical upper bounds for the relative efficiency of a large class of crossover designs, the totally balanced designs, under a model with the baseline covariates as compared with the model without the baseline covariates. We present numerical details based on these bounds for assorted scenarios and reveal implications of these results. Copyright © 2012 John Wiley & Sons, Ltd.     

MRI findings of optic pathway involvement in Miller Fisher syndrome in 3 pediatric patients and a review of the literature

Background: Miller Fisher syndrome (MFS) is a rare demyelinating condition which may have involvement of cranial nerves. There are a few case reports of optic pathway involvement in children. We describe 3 patients with optic pathway enhancement in pediatric patients with MFS. Case series: We retrospectively reviewed brain imaging findings in 17 pediatric patients with of Guillain–Barré syndrome (GBS) meeting Brighton criteria who had brain MRIs performed during their acute illness. Cranial nerve enhancement was seen in 6/17 patients and optic nerve/chiasm enhancement was seen in 3 patients. Conclusion: Cranial nerve enhancement and optic pathway in particular, can be seen in patients with MFS. Imaging findings do not always correlate with clinical manifestations of cranial nerve involvement.