bluuebunny/crossref_metadata_2025_split huggingface dataset:
SNP Subset Selection for Genetic Association Studies
Authors: Byng M. C. , Whittaker J. C. , Cuthbert A. P. , Mathew C. G. , Lewis C. M. 
Published: November 2003

SummaryAssociation studies for disease susceptibility genes rely on the high density of SNPs within candidate genes. However, the linkage disequilibrium between SNPs imply that not all SNPs identified in the candidate region need be genotyped. Here we develop several approaches to SNP subset selection, which can substantially reduce the number of SNPs to be genotyped in an association study. We apply clustering algorithms to pairwise linkage disequilibrium measures, with SNP subsets determined for different cut‐off values of Δ using nearest and furthest neighbour clusters. Alternatively, SNP subsets may be determined by the proportion of haplotypes they identify. We also show how power calculations, based on the average power to identify a SNP as the disease susceptibility mutation using haplotype‐based or logistic regression based statistical analyses, can be used to choose SNP subsets. All these methods provide a ranking method for subsets of a specific size, but do not provide criteria for overall choice of SNP subset size. We develop such criteria by incorporating power calculations into a decision analysis, where the choice of SNP subset size depends on the genotyping costs and the perceived benefits of identifying association. These methods are illustrated using eleven SNPs in the MMP2 gene.
Power of Linkage Disequilibrium Mapping to Detect a Quantitative Trait Locus (QTL) in Selected Samples of Unrelated Individuals
Authors: Tenesa A. , Knott S. A. , Carothers A. D. , Visscher P. M. 
Published: November 2003

SummaryWe considered a strategy to map quantitative trait loci (QTLs) using linkage disequilibrium (LD) when the QTL and marker locus were multiallelic. The strategy involved phenotyping a large number of unrelated individuals and genotyping only selected individuals from the two tails of the trait distribution. Power to detect trait‐marker association was assessed as a function of the number of QTL and marker alleles. Two patterns of LD were used to study their influence on power. When the frequency of the QTL allele with the largest effect and that of the marker allele linked in coupling were equal, power was maximum. In this case, increasing the number of QTL alleles reduced the power. The maximum difference in power between the two LD patterns studied was ∼30%. For low QTL heritabilities (h2QTL < 0.1) and single trait studies we recommend selecting around 5% of the upper and lower tails of the trait distribution.
A 34 bp Deletion WithinTSC2is a Rare Polymorphism, not a Pathogenic Mutation
Authors: Roberts Penelope S. , Ramesh Vijaya , Dabora Sandra , Kwiatkowski David J. 
Published: November 2003

SummaryTuberous sclerosis (TSC) is an autosomal dominant hamartoma syndrome due to mutations in eitherTSC1orTSC2. Previous reports have identified a mutation consisting of a 34 bp deletion affecting portions of exon 38 and the adjacent intron 38 ofTSC2. We found this genetic variation in 4 of 800 TSC patients screened for mutations inTSC1andTSC2. In every case, the variant was present in one unaffected parent of the sporadically affected TSC child. By RT‐PCR analysis of RNA samples from two additional families with this genetic variant, we demonstrate that the allele with the deletion generates about 50% normal RNA transcript, and 50% RNA transcript including intron 38. In addition, there is no correlation between the extent of splicing and clinical status of family members. We also excluded the possibility of mosaicism in the parents with this variant. We conclude that this deletion is a rare polymorphism that does not cause TSC, but may be a modifier of the TSC phenotype.
An Analysis of Consanguinity and Social Structure Within the UK Asian Population Using Microsatellite Data
Authors: Overall A. D. J. , Ahmad M. , Thomas M. G. , Nichols R. A. 
Published: November 2003

SummaryWe analysed microsatellite genotypes sampled from the Pakistani and Indian communities in Nottingham, UK, to investigate the genetic consequences of substructuring mediated by traditional marriage customs. The application of a recently developed likelihood approach identified significant levels of population substructure within the Pakistani community as a whole, as well as within the finer divisions of castes and biradheri. In addition, high levels of cryptic or unacknowledged consanguinity were detected within subgroups of this community, including biradheri. The Indian sample showed no significant evidence of either substructure or consanguinity. We demonstrate that estimates of disease gene frequencies can be inaccurate unless they are made jointly with estimates of population substructure and consanguinity ((θ≡FST) and C). The magnitude of these estimates also highlights the importance of accounting for the finer scale of social structuring when making decisions regarding the risk of recessive disorders in offspring.
Testing the Genetic Relation Between Two Individuals Using a Panel of Frequency‐unknown Single Nucleotide Polymorphisms
Authors: Lee W.‐C. 
Published: November 2003

SummaryThe author proposes a method to test the genetic relation between two individuals using a panel of SNPs. The method does not require information about the allele frequencies, and as such it can be used to test any pair of individuals from any population(s).
Tests for Candidate‐Gene Association Using Case‐Parents Design
Authors: Zheng G. , Chen Z. , LI Z. 
Published: November 2003

SummaryIn the case‐parents design for testing candidate‐gene association, the conditional likelihood method based on genotype relative risks has been developed recently. A specific relation of the genotype relative risks is referred to as a genetic model. The efficient score tests have been used when the genetic model is correctly specified under the alternative hypothesis. In practice, however, it is usually not able to specify the genetic model correctly. In the latter situation, tests such as the likelihood ratio test (LRT) and the MAX3 (the maximum of the three score statistics for dominant, additive, and recessive models) have been used. In this paper, we consider the restricted likelihood ratio test (RLRT). For a specific genetic model, simulation results demonstrate that RLRT is asymptotically equivalent to the score test, and both are more powerful than the LRT. When the genetic model cannot be correctly specified, the simulation results show that RLRT is most robust and powerful in the situations we studied. MAX3 is the next most robust and powerful test. The TDT is the easiest statistic to compute, compared to MAX3 and RLRT. When the recessive model can be eliminated, it is also as robust and powerful as RLRT for other genetic models.
A Note on Including Phenotypic Information from Monozygotic Twins in Variance Components Qtl Linkage Analysis
Authors: Evans D. M. , Medland S. E. 
Published: November 2003

Summary Williams & Blangero (1999) derived closed form expressions for the power of a univariate variance components test of linkage for a variety of pedigree structures. We have extended their results by investigating the effect of including monozygotic twins in the design on the power to detect linkage. Specifically, we determined the power associated with a pedigree of size three, where individuals one and two were monozygotic twins and individual three was a full sibling to the twins. The power of this sampling unit was uniformly greater than the power obtained from a sib‐pair under the same genetic model. The reason for this was that addition of a second monozygotic twin provided another estimate of the sibling correlation for the particular IBD class. In addition, when the total heritability of the trait was <50%, the number of individuals that needed to be phenotyped was less than that with sib‐pairs alone. However, a pedigree consisting of a monozygotic pair and sibling was never as informative as a sib‐trio, presumably because the sib‐trio provided information about allele sharing between three individuals, whereas the monozygotic twins and sibling unit only provided one such relationship. We conclude that including a monozygotic twin in the analysis is an economical strategy, since only one twin needs to be genotyped.
Evaluating the potential health gain of the World Health Organization's recommendation concerning vegetable and fruit consumption
Authors: Hoffmann Kurt , Boeing Heiner , Volatier Jean-Luc , Becker Wulf 
Published: November 2003

AbstractObjective:The World Health Organization (WHO) recommends a daily intake of at least 400?g of vegetables and fruit. The aim of this paper was to evaluate the public health benefit of meeting this WHO recommendation by applying a statistical method that combines estimated intake distributions and simulated intake changes.Design and setting:The benefit of an increased consumption of vegetables and fruit was quantified by the preventable proportion of diseases. This proportion was estimated by a general formula derived in the paper that incorporates individual relative risks. Three different strategies of increasing usual intake were simulated and compared. The first strategy assumes that all individuals increase their intake by the same amount, the second assumes a constant increase among low consumers, and the third simulates individual increments necessary to meet the WHO recommendation. Calculations were made for three different scenarios with varying relative risks.Results:The third simulation strategy turned out to be the most appropriate one to quantify the potential health gain of the current dietary recommendation. Applying this strategy to prevent cancer, the proportion of preventable cases was country-specific. Estimates for France and Sweden were 21.9% and 19.3%, respectively, which are somewhat lower than the non-specific figure published by the World Cancer Research Fund.Conclusions:To improve estimates of the preventable proportion of diseases, the estimation formula presented here can be applied. Its application requires intake data to estimate the initial intake distribution in the population and to simulate adequate dietary changes.
The Reform of Local Public Utilities in Italy
Authors: Bognetti G. , Robotti L. 
Published: November 2003

The Italian system of local public utilities has recently undergone an important reform process. The first round of reforms, introduced in the 1990s, represented a remarkable change in the social welfare function with regard to the management of local public utilities. The legislation was specifically designed to cut costs and reduce deficits. A second round of reforms, required by European directives, started around the mid‐1990s. Several laws were passed introducing important innovations and regulating specific sectors: public transport; electricity; and gas. Article 35 of the 2002 Financial Law was the final step in a comprehensive reform of the whole local public utility sector. The main innovations of the Financial Law concerns liberalization. Article 35 states that the general rule for awarding service provision contracts is competitive tendering; the rationale is obviously that of competition for the market. The general rule as expressed by Article 35 is nevertheless limited during the transition period. In the long run, competitive tendering will become the normal way of awarding contracts for local public utility provision. Even if there are doubts that full competition will be introduced into the sector, liberalization does appear to be having an effect, forcing many local public utilities to become more efficient. The changes introduced have brought about a better and a more efficient system with a greater number of large size enterprises and on the average a more active management.In the future, the liberalization process may come to a standstill due to an insufficient number of competitors. Strong public administrations are therefore needed to prevent opportunistic behaviour by private firms.
Levetiracetam and Partial Seizure Subtypes: Pooled Data from Three Randomized, Placebo‐controlled Trials
Authors: Leppik Ilo E. , Biton Victor , Sander Josemir W. A. , Wieser Heinz Gregor 
Published: November 2003

Summary:  Purpose: To determine the effect of levetiracetam (LEV) on partial seizure subtypes (simple partial, complex partial, and secondarily generalized seizures) in patients with refractory epilepsy. Methods: Pooled results from three placebo‐controlled trials were analyzed. Results: A statistically significant reduction in the frequency of all partial seizures and all seizure subtypes was observed in the LEV group (p < 0.001 vs. placebo). The proportion of patients in whom secondarily generalized seizures could be prevented over and above the reduction of partial seizures was significantly greater in the LEV group as compared with placebo, with an odds ratio of 1.83 [95% confidence interval (CI), 1.10–3.05]. Conclusions: LEV reduces frequency of simple and complex partial seizures. In addition, it demonstrates a specific, independent reduction of secondarily generalized seizures.
The Role of Hippocampal Sclerosis in Topiramate‐related Depression and Cognitive Deficits in People with Epilepsy
Authors: Mula Marco , Trimble Michael R. , Sander Josemir W. A. S. 
Published: November 2003

Summary:  Purpose: To clarify the role of hippocampal sclerosis (HS) in developing psychiatric and cognitive adverse events during therapy with topiramate (TPM) in patients with temporal lobe epilepsy (TLE). Methods: We analyzed the data of 70 patients with TLE and HS and 128 patients with cryptogenic TLE matched for age, sex, starting dose, and titration schedule of TPM. They were selected from the first consecutive 431 patients started on TPM between 1995 and 1999. Results: Patients with HS were more likely to develop cognitive adverse events (CAEs; p = 0.002) and depression (p = 0.018) and to be receiving a polytherapy regimen (p = 0.007). However, regression analysis demonstrated that only HS was a predictive factor for the occurrence of CAEs (OR = 2.4; p < 0.001) and depression (OR = 2.3; p = 0.02). Conclusions: Patients with TLE and HS were more prone to develop CAEs and depression than were patients with cryptogenic TLE, during TPM therapy, despite the same titration schedule. The presence of HS and not duration of epilepsy or polytherapy regimen represented the main risk factor.
Vagal Nerve Stimulation Induces Intermittent Hypocapnia
Authors: Holmes Mark D. , Miller John W. , Voipio Juha , Kaila Kai , Vanhatalo Sampsa 
Published: November 2003

Summary:  Purpose: To study whether respiratory alteration caused by vagal nerve stimulation (VNS) can change end‐tidal carbon dioxide (EtCO2) levels. Methods: We performed polygraphic recordings including capnographic monitoring during daytime sleep on adults with VNS therapy. Results: Ten of 13 patients showed VNS‐induced alterations in the frequency or amplitude of respiration. Five patients had a consistent increase in respiratory rate with a simultaneous, consistent and significant decrease (p < 0.01; 5–22%) in EtCO2 during VNS. Three subjects showed occasional decreases in EtCO2 during VNS, and two showed no clearly detectable VNS‐related EtCO2 changes. Conclusions: Our findings suggest that VNS may alter brain CO2 levels through changes in respiration. Because carbon dioxide (CO2) has potent effects on various brain functions, it is possible that these transient CO2 changes may have an effect on the state transitions between interictal and preictal states.
Long‐lasting Anticonvulsant Effect of Focal Cooling on Experimental Neocortical Seizures
Authors: Yang Xiao‐Feng , Chang Jong Hee , Rothman Steven M. 
Published: November 2003

Summary:  Purpose: Previous clinical and experimental observations have demonstrated that cooling the brain can rapidly terminate focal seizures. We wished to determine whether cooling at regular intervals could prevent or attenuate the development of seizures in a model of focal epilepsy. Methods: We induced focal neocortical seizures in halothane‐anesthetized rats by the microinjection of 4‐aminopyridine (4‐AP) into the motor cortex. With a small thermoelectric device, the site of the 4‐AP injection was either cooled intermittently (PostCool) for 30 s every 2 min, starting 15 min after the 4‐AP injection, or precooled (PreCool) for 30 min before 4‐AP injection, by using the same 30‐s cooling cycle. Seizures were quantified in 30‐min observation periods for 1.5 h. Results: The average durations of PostCool and PreCool seizures were shorter than those of controls (p < 0.001). In addition, total seizure duration was significantly reduced in both groups, compared with controls (p < 0.01). The ratio of the root mean square power during a seizure to power in the immediate preseizure period was reduced in both PostCool and PreCool groups (p < 0.001). The number of seizures significantly declined over a 30‐ to 60‐min period in both experimental groups, and by 60 min, no seizures were evident. Conclusions: These experiments show that gentle cooling to 20°C is capable of markedly reducing subsequent seizure frequency and intensity. The effects in our model, which generates very frequent and intense ictal activity, were robust, suggesting that prophylactic cooling might be even more beneficial in clinical situations. The physiologic mechanism for this preventive effect requires elucidation.
Increased Persistent Sodium Currents in Rat Entorhinal Cortex Layer V Neurons in a Post–Status Epilepticus Model of Temporal Lobe Epilepsy
Authors: Agrawal Newton , Alonso Angel , Ragsdale David S. 
Published: November 2003

Summary:  Purpose: Spontaneous seizures in rats emerge several weeks after induction of status epilepticus with pharmacologic treatment or electrical stimulation, providing an animal model for human temporal lobe epilepsy. In this study, we investigated whether status epilepticus caused changes in the function of voltage‐gated sodium channels in entorhinal cortex layer V neurons, a cellular group important for the genesis of limbic seizures. Methods: We induced status epilepticus in rats, by using lithium‐pilocarpine, and then 2–12 weeks later, used whole‐cell voltage‐clamp to examine voltage‐activated sodium currents of acutely dissociated layer V neurons. Results: Transient sodium currents of entorhinal cortex layer V neurons isolated from 9‐ to 12‐week post–status epilepticus rats were similar to currents in age‐matched controls; however, low‐threshold persistent sodium currents were significantly larger. This increase in persistent activity was not seen 2–3 weeks after pilocarpine treatment; thus it occurred after a delay comparable to the delay in the appearance of spontaneous seizures. Conclusions: Increased persistent currents are expected to accentuate neuronal excitability and thus may contribute to the genesis of spontaneous seizures after status epilepticus.
Single‐unit Analysis of Substantia Nigra Pars Reticulata Neurons in Freely Behaving Rats with Genetic Absence Epilepsy
Authors: Deransart Colin , Hellwig Bernhard , Heupel‐Reuter Miriam , Léger Jean‐François , Heck Detlef , Lücking Carl Hermann 
Published: November 2003

Summary:  Purpose: The substantia nigra pars reticulata (SNpr) is assumed to be involved in the control of several kinds of epileptic seizures, an assumption based mostly on neuropharmacologic evidence. However, only very few neurophysiological recordings from the basal ganglia support neuropharmacologic data. We investigated the electrophysiologic activity of SNpr neurons in rats with genetic absence epilepsy. Methods: Electrocorticography (ECoG) and multi‐unit recordings using permanently implanted tetrodes were obtained in freely behaving rats. After spike sorting, auto‐ and cross‐correlation analysis was used to detect oscillatory neuronal activities and synchronizations. Results: During interictal periods, neither oscillation nor synchronization could be observed in the firing patterns of SNpr neurons. At the beginning of the absence seizure, the firing rate increased significantly. The SNpr neurons started firing in bursts of action potentials. Bursts were highly correlated to the spike‐and‐wave discharges (SWDs) in the ECoG, mainly after the spike component of the cortical spike‐and‐wave complex. Moreover, pairs of SNpr neurons tended to fire synchronously. Before the end of the seizure, the firing rate decreased progressively, and the burst‐firing pattern ended at or before the end of the SWDs. Once the SWDs had stopped, the SNpr neurons resumed their basal firing pattern as before the seizure onset. Conclusions: These results provide electrophysiologic evidence that firing patterns and synchronization of SNpr neurons are in phase with the occurrence of SWDs. The findings support the concept that nigral control mechanisms are involved in modulating the propagation of an ongoing generalized seizure.
Texture Analysis of Hippocampal Sclerosis
Authors: Bonilha Leonardo , Kobayashi Eliane , Castellano Gabriela , Coelho Giselle , Tinois Eduardo , Cendes Fernando , Li Li M. 
Published: November 2003

Summary:  Mesial temporal lobe epilepsy (MTLE) is frequently associated with refractory seizures and pathologic features of hippocampal sclerosis (HS). Quantitative magnetic resonance imaging (MRI) techniques can improve the detection and quantification of HS. The objective of this study was to evaluate whether MRI texture analysis can detect hippocampal abnormalities in patients with pathologically proven HS. Methods: Nineteen consecutive patients who underwent surgery for refractory unilateral MTLE and had HS diagnosed on histopathology (12 right and seven left) had their preoperative MRIs evaluated. We performed texture analysis in 3‐mm coronal T1‐IR MRIs, focusing on the hippocampal head, by using the software MAZDA. Data were compared with those of a group of 78 normal hippocampi from 39 healthy adult volunteers through multivariate analysis of variance and selection of the most significant texture parameters. Results: Overall, almost all parameters of texture could discriminate the group of hippocampi with HS and the group of contralateral hippocampi from the group of normal hippocampi, but the post hoc comparison showed no differences between HS and contralateral hippocampi. Conclusions: These results provide evidence of texture alteration in MRIs of hippocampi with HS and corroborate the hypothesis of bilaterality of hippocampal damage in patients with MTLE, but further studies are needed to investigate the lateralization power of texture analysis.