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At least 19 recordsLinked to original sources
PubMed1992

Meta-analysis of second-line antirheumatic drugs: sample size bias and uncertain benefit.

Placebo controlled trials of methotrexate, auranofin, penicillamine, azathioprine, sulphasalazine, gold sodium thiomalate and chloroquines were subjected to meta-analysis. The difference between drugs and placebo in the erythrocyte sedimentation rate was 8.8 mm/hr [95% confidence interval (CI), 6.4-11.3]. In multiple linear regression analyses, with the physician's global evaluation and relative change in joint tenderness count as outcome variables, a substantial sample size bias was demonstrated. The effect decreased with increasing sample size. The risk of dropping out from any cause was larger on drug than on placebo (odds ratio, 1.17; CI, 0.99-1.38). No evidence of a worthwhile effect on radiological changes was found. Of the 3439 patients, 4 went into complete remission on drug. We conclude that the benefit of second-line drugs is uncertain.

Arthritis, Rheumatoid↗
PubMed2006

Size bias of fragile X premutation alleles in late-onset movement disorders.

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS), caused by premutation expansions (55-200 CGG repeats) of the FMR1 gene, shares clinical features with other movement disorders, particularly in the domains of gait ataxia, intention tremor and parkinsonism. However, the prevalence of FXTAS within other diagnostic categories is not well defined. METHODS: A meta-analysis was conducted of all published (n = 14) genetic screens for expanded FMR1 alleles to assess the prevalence and CGG-repeat size bias of FMR1 premutation alleles in those populations. RESULTS: In men with late-onset cerebellar ataxia, the prevalence of premutation alleles (1.5%; 16/1049) was 13 times greater than expected based on its prevalence in the general population (2%; 16/818 for age of onset >50 years; odds ratio 12.4; 95% confidence interval 1.6 to 93.5). Meta-analysis of CGG-repeat data for screened patients with premutation alleles shows a shift to larger repeat size than in the general population (p<0.001). 86% (19/22) of premutation alleles were larger than 70 repeats in the patients screened, whereas only approximately 22% of premutation alleles are larger than 70 repeats in the general population. CONCLUSIONS: Expanded FMR1 alleles contribute to cases of late-onset sporadic cerebellar ataxia, suggesting that FMR1 genetic testing should be carried out in such cases. The biased distribution of FMR1 allele sizes has substantial implications for genetic counselling of carriers with smaller alleles who are at a low risk of developing FXTAS, and suggests that the estimated prevalence of FXTAS among men >50 years of age in the general population may be two to threefold lower than the initial figure of 1 in 3000.

Adult↗
PubMed1991

Polyamines eliminate an extreme size bias against transformation of large yeast artificial chromosome DNA.

The recent development of vectors and methods for cloning large linear DNA as yeast artificial chromosomes (YACs) has enormous potential in facilitating genome analysis, particularly because of the large cloning capacity of the YAC cloning system. However, the construction of comprehensive libraries with very large DNA segments (400-500 kb average insert size) has been technically very difficult to achieve. We have examined the possibility that this difficulty is due, at least in part, to preferential transformation of the smaller DNA molecules in the yeast transformation mixture. Our data indicate that the transformation efficiency of a 330-kb linear YAC DNA molecule is 40-fold lower, on a molar basis, than that of a 110-kb molecule. This extreme size bias in transformation efficiency is dramatically reduced (to less than 3-fold) by treating the DNA with millimolar concentrations of polyamines prior to and during transformation into yeast spheroplasts. This effect is accounted for by a stimulation in transformation efficiency of the 330-kb YAC molecule; the transformation efficiency of the 110-kb YAC molecule is not affected by the inclusion of polyamines. Application of this finding to the cloning of large exogenous DNA as artificial chromosomes in yeast will facilitate the construction of genomic libraries with significantly increased average insert sizes. In addition, the methods described allow efficient transfer of YACs to yeast strain backgrounds suitable for subsequent manipulations of the large insert DNA.

Chromosomes, Fungal↗
PubMed2004

Inbreeding coefficients for stochastically varying small population sizes-bias of calculation based on effective numbers.

The commonly used procedure to calculate inbreeding coefficients by effective population numbers (Ne) by the harmonic mean of generation-by-generation population sizes involves a computational bias. If the individual population sizes are considered as realizations of a binomially distributed random variable with sample size N and probability p, this bias can be investigated for the two cases p = constant and p = variable (Markov chain). The bias is of practical relevance only for small probabilities p, short period of initial successive generations, and small population sizes. The largest values for this computational bias are in the range of 0.05-0.06. It is concluded that for most practical purposes the approximate procedure is appropriate.

Animals↗
PubMed2006

Population size bias in descendant-weighted diffusion quantum Monte Carlo simulations.

We consider the influence of population size on the accuracy of diffusion quantum Monte Carlo simulations that employ descendant weighting or forward walking techniques to compute expectation values of observables that do not commute with the Hamiltonian. We show that for a simple model system, the d-dimensional isotropic harmonic oscillator, the population size must increase rapidly with d in order to ensure that the simulations produce accurate results. When the population size is too small, expectation values computed using descendant-weighted diffusion quantum Monte Carlo simulations exhibit significant systematic biases.

Journal Article↗
PubMed2002

Female-biased sexual size dimorphism in the yellow-pine chipmunk (Tamias amoenus): sex-specific patterns of annual reproductive success and survival.

Sexual size dimorphism is ultimately the result of independent, sex-specific selection on body size. In mammals, male-biased sexual size dimorphism is the predominant pattern, and it is usually attributed to the polygynous mating system prevalent in most mammals. This sole explanation is unsatisfying because selection acts on both sexes simultaneously, therefore any explanation of sexual size dimorphism should explain why one sex is relatively large and the other is small. Using mark-recapture techniques and DNA microsatellite loci to assign parentage, we examined sex-specific patterns of annual reproductive success and survival in the yellow-pine chipmunk (Tamias amoenus), a small mammal with female-biased sexual size dimorphism, to test the hypothesis that the dimorphism was related to sex differences in the relationship between body size and fitness. Chipmunks were monitored and body size components measured over three years in the Kananaskis Valley, Alberta, Canada. Male reproductive success was independent of body size perhaps due to trade-offs in body size associated with behavioral components of male mating success: dominance and running speed. Male survival was consistent with stabilizing selection for overall body size and body size components. The relationship between reproductive success and female body size fluctuated. In two of three years the relationship was positive, whereas in one year the relationship was negative. This may have been the result of differences in environmental conditions among years. Large females require more energy to maintain their soma than small females and may be unable to maintain lactation in the face of challenging environmental conditions. Female survival was positively related to body size, with little evidence for stabilizing selection. Sex differences in the relationship between body size and fitness (reproductive success and survival) were the result of different processes, but were ultimately consistent with female-biased sexual size dimorphism evident in this species.

Animals↗
PubMed1983

Is there a bias in size measurements taken from mirror-reversed photographs of body parts?

This study compared measurements of hands, feet, and hemifaces taken from original and mirror-reversed photographs to determine whether a hemispace-bias exists in size measurements. Posers were adult right- and left-handers (50% female). In 80% of the measurement comparisons (total N = 84), there was complete agreement; there were no instances of right-left reversals among the discrepant comparisons. The side of the body measured as larger was independent of the side of space in which it appeared. The lack of such bias in physical measurements is discrepant with data suggesting a left-hemispace preference in psychological judgments of visual material.

Adult↗
PubMed1997

Limitations to the robustness of binormal ROC curves: effects of model misspecification and location of decision thresholds on bias, precision, size and power.

This paper concerns robustness of the binormal assumption for inferences that pertain to the area under an ROC curve. I applied the binormal model to rating method data sets sampled from bilogistic curves and observed small biases in area estimates. Bias increased as the range of decision thresholds decreased. The variance of area estimates also increased as the range of decision thresholds decreased. Together, minor bias and inflated variance substantially altered the size and power of statistical tests that compared areas under bilogistic ROC curves. I repeated the simulations by applying the binormal assumption to data sampled from binormal curves. Biases in area estimates were minimal for the binormal data, but the variance of area estimates was again higher when the range of decision thresholds was narrow. The size of tests that compared areas did not vary from the chosen significance level. Power fell, however, when the variance of area estimates was inflated. I conclude that inferences derived from the binormal assumption are sensitive to model misspecification and to the location of decision thresholds. A narrow span of decision thresholds increases the variability of area estimates and reduces the power of area comparisons. Model misspecification produces bias that alters test size and can exaggerate the loss of power that accompanies increased variability.

Bias↗
PubMedDate not supplied

Analysis and display of the size dependence of chemical similarity coefficients.

We discuss the size-bias inherent in several chemical similarity coefficients when used for the similarity searching or diversity selection of compound collections. Limits to the upper bounds of 14 standard similarity coefficients are investigated, and the results are used to identify some exceptional characteristics of a few of the coefficients. An additional numerical contribution to the known size bias in the Tanimoto coefficient is identified. Graphical plots with respect to relative bit density are introduced to further assess the coefficients. Our methods reveal the asymmetries inherent in most similarity coefficients that lead to bias in selection, most notably with the Forbes and Russell-Rao coefficients. Conversely, when applied to the recently introduced Modified Tanimoto coefficient our methods provide support for the view that it is less biased toward molecular size than most. In this work we focus our discussion on fragment-based bit strings, but we demonstrate how our approach can be generalized to continuous representations.

Journal Article↗
PubMed2001

Balanced-size and long-size cloning of full-length, cap-trapped cDNAs into vectors of the novel lambda-FLC family allows enhanced gene discovery rate and functional analysis.

We have developed a new class of cloning vectors: lambda-full-length cDNA (lambda-FLC) cloning vectors. These vectors can be bulk-excised for preparing full-length cDNA libraries in which a high proportion of the plasmids carry large inserts that can be transferred into other (for example, functional) vectors. Unlike other cloning vectors, lambda-FLC vectors accommodate a broad range of sizes of eukaryotic cDNA inserts because they contain "size balancers." Further, the main protocol we use for direct bulk excision of plasmids is mediated by a Cre-lox system and is apparently free of size bias. The average size of the inserts from excised plasmid cDNA libraries was 2.9 kb for standard and 6.9 kb for size-selected cDNA. The average insert size of the full-length cDNA libraries was correlated to the rate of new gene discovery, suggesting that effectively cloning rarely expressed mRNAs requires vectors that can accommodate large inserts from a variety of sources. Part of the vectors are also suitable for bulk transfer of inserts into various functional vectors.

Animals↗
PubMed2005

CDNA library construction from a small amount of RNA: adaptor-ligation approach for two-round cRNA amplification using T7 and SP6 RNA polymerases.

In this study, we developed a method that allows cDNA library construction from a small amount of RNA without causing serious size bias in the resulting cDNA population. For this purpose, we adopted two-round cRNA amplification by T7 and SP6 RNA polymerases. The first-round cDNAs, flanked by the promoter sequences of T7 and SP6 RNA polymerases, were synthesized from 1 microg total RNA and then subjected to two rounds of cRNA amplification. Comparison of the sizes of the first-round and the second-round cRNAs indicated that the size-bias effect of the second-round cRNA synthesis was not serious. The resultant double-stranded cDNAs were cloned into a plasmid by in vitro lambda phage recombination with an efficiency of 1.2 x 10(11) colony-forming unit/microgram of starting total RNA. Characterization of the resultant cDNA library in terms of the insert size, clone redundancy, and integrity of 3' ends of cDNAs indicated that the amplified library was comparable to a library constructed by a conventional method, although large cDNAs tend to be slightly truncated in the amplified library. This method enables the construction of a library from a small amount of RNA, and calculations suggest that the strategy would be efficient enough to use even a single cell as starting material.

Cloning, Molecular↗
PubMed1999

The hidden component of size in two-dimensional fragment descriptors: side effects on sampling in bioactive libraries.

We have carried out a number of sampling experiments in libraries of bioactive compounds to illustrate how size biases introduced by two-dimensional (2D) fragment distance functions may provide misleading information about the diversity of compound subsets. The number of different biological targets covered by a given subset is used as a measure of bioactive diversity, and it is considered to be the relevant property with which 2D diversity should correlate. Since the nature of the size biases depends on the way in which 2D distance is computed, we investigated three different methods of calculating distance. Use of 1-Tanimoto as a dissimilarity measure leads to the spurious conclusion that collections of structurally small compounds are inherently more diverse than other collections which may cover a broader range of sizes and more biological targets. XOR or squared Euclidean distance, by contrast, shows a preference for subsets of structurally larger compounds, but this does not appear to have as many adverse consequences in terms of target coverage. A simple product of 1-Tanimoto and XOR tends to equalize the opposing size effects of the two component distance functions and leads to a relatively unbiased means of comparing structures. Results here suggest that careful consideration should be given to the way in which chemical structures are compared whenever 2D fragment descriptors are used.

Drug Design↗
PubMed2006

Compositional bias and size of genomes of human DNA viruses.

Genomes of 144 human DNA viruses were analyzed in the aspect of their compositional asymmetry. DNA viruses were divided into two groups according to their genome sizes. The analysis revealed that the level of guanine and cytosine (GC content) in the coding sequences of small genome DNA viruses was significantly lower than that of large genome DNA viruses. Because small genome viruses replicate their genomes using cellular enzymes, while large genome viruses use their own enzymes for genome replication, the two groups of viruses may be under different mutational bias and/or selection pressure. In these viruses, GC content at the third codon position correlated with GC content at the first and second codon position. However, the relationship in small genome DNA viruses was weaker than that in large genome DNA viruses, suggesting that their genome composition may be more strongly influenced by codon usage preference or restriction on amino acid composition.

Base Composition↗
PubMed2003

Placebo treatment versus no treatment.

BACKGROUND: Placebo interventions are often believed to improve patient reported and observer reported outcomes, but this belief is not based on evidence from randomised trials that compare placebo with no treatment. OBJECTIVES: To assess the effect of placebo interventions. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register (The Cochrane Library, issue 3, 1998), MEDLINE (Jan 1966 to Dec 1998), EMBASE (Jan 1980 to Dec 1998), Biological Abstracts (Jan 1986 to Dec 1998), PsycLIT (Jan 1887 to Dec 1998). Experts on placebo research were contacted and references in the included trials were read. SELECTION CRITERIA: Randomised placebo trials with a no-treatment control group investigating any health problem were included. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. MAIN RESULTS: Outcome data were available in 114 out of 130 included trials, investigating 40 clinical conditions. Outcomes were binary in 32 trials (3795 patients) and continuous in 82 (4730 patients). We found no statistically significant pooled effect of placebo in studies with binary outcomes, relative risk 0.95 (95 per cent confidence interval 0.88 to 1.02). The pooled relative risk for subjective (patient reported) outcomes was 0.95 (0.86 to 1.05) and for objective (observer reported) outcomes 0.91 (0.80 to 1.04). There was statistically significant heterogeneity (P < 0.03), but no evidence of sample size bias (P = 0.56). We found an overall positive effect of placebo treatments in trials with continuous outcomes, standardised mean difference -0.28 (95 per cent confidence interval -0.38 to -0.19). The standardised mean difference for subjective outcomes was -0.36 (-0.47 to -0.25), whereas no statistically significant effect was found for objective outcomes, standardised mean difference -0.12 (-0.27 to 0.03). There was statistically significant heterogeneity (P < 0.001), and evidence of sample size bias (P = 0.05). There was no statistically significant effect of placebo interventions in eight out of nine clinical conditions investigated in three trials or more (nausea, relapse in prevention of smoking and depression, overweight, asthma, hypertension, insomnia and anxiety), but confidence intervals were wide. There was a modest apparent analgesic effect of placebo interventions, standardised mean difference -0.27 (-0.40 to -0.15), but also a substantial risk of bias. REVIEWER'S CONCLUSIONS: There was no evidence that placebo interventions in general have clinically important effects. A possible moderate effect on subjective continuous outcomes, especially pain, could not be clearly distinguished from bias.

Humans↗
PubMedDate not supplied

Relationships between Molecular Complexity, Biological Activity, and Structural Diversity.

Following the theoretical model by Hann et al. moderately complex structures are preferable lead compounds since they lead to specific binding events involving the complete ligand molecule. To make this concept usable in practice for library design, we studied several complexity measures on the biological activity of ligand molecules. We applied the historical IC50/EC50 summary data of 160 assays run at Novartis covering a diverse range of targets, among them kinases, proteases, GPCRs, and protein-protein interactions, and compared this to the background of "inactive" compounds which have been screened for 2 years but have never shown any activity in any primary screen. As complexity measures we used the number of structural features present in various molecular fingerprints and descriptors. We found generally that with increasing activity of the ligands, their average complexity also increased, and we could therefore establish a minimum number of structural features in each descriptor needed for biological activity. Especially well suited in this context were the Similog keys and circular substructure fingerprints. These are those descriptors, which also perform especially well in the identification of bioactive compounds by similarity search, suggesting that structural features encoded in these descriptors have a high relevance for bioactivity. Since the number of features correlates with the number of atoms present in the molecule, also the number of atoms serves as a reasonable complexity measure and larger molecules have, in general, higher activities. Due to the relationship between feature counts and densities on one hand and biological activity on the other, the size bias present in almost all similarity coefficients becomes especially important. Diversity selections using these coefficients can influence the overall complexity of the resulting set of molecules, which has an impact on the biological activity that they exhibit. Using sphere-exclusion based diversity selection methods, such as OptiSim together with the Tanimoto dissimilarity, the average feature count distribution of the resulting selections is shifted toward lower complexity than that of the original set, particularly when applying tight diversity constraints. This size bias reduces the fraction of molecules in the subsets having the complexity required for a high, submicromolar activity. None of the diversity selection methods studied, namely OptiSim, divisive K-means clustering, and self-organizing maps, yielded subsets covering the activity space of the IC50 summary data set better than subsets selected randomly.

Drug Design↗