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PubMed2003

Single-nucleotide polymorphisms in the Toll-like receptor 9 gene (TLR9): frequencies, pairwise linkage disequilibrium, and haplotypes in three U.S. ethnic groups and exploratory case-control disease association studies.

TLR9 is a mammalian Toll-like receptor homologue that appears to function as an innate immune pattern recognition protein for motifs that are far more common in bacterial than in mammalian DNA. The gene was sequenced in 71 subjects from three self-identified U.S. ethnic groups to identify single-nucleotide polymorphisms (SNPs). A total of 20 SNPs were found of which only 20% were in the public dbSNP database. Four SNPs were relatively common in all three ethnic samples. Using these four SNPs, seven distinct haplotypes were statistically inferred, of which four accounted for 75% or more chromosomes. These four haplotypes could be distinguished from each other by the alleles of two SNPs (-1237 and 2848). Five exploratory nested case-control disease-association studies (asthma, DVT, MI, and COPD in European Americans and asthma in African Americans) were performed by genotyping DNA collected from four ongoing cohort studies. There was evidence suggesting increased risk for asthma with a C allele at -1237 (odds ratio 1.85, 95%CI 1.05 to 3.25) among European Americans (genotypes available from 67 cases and 152 controls). No other significant disease associations were detected. Replication of this finding in other, larger samples is needed. This study suggests that there is substantial diversity in human TLR9, possibly associated with asthma in Europeans but not African Americans. No association was detected with three other diseases potentially related to innate immunity.

Black People↗

PubMed2003

Singularities in mixture models and upper bounds of stochastic complexity.

A learning machine which is a mixture of several distributions, for example, a gaussian mixture or a mixture of experts, has a wide range of applications. However, such a machine is a non-identifiable statistical model with a lot of singularities in the parameter space, hence its generalization property is left unknown. Recently an algebraic geometrical method has been developed which enables us to treat such learning machines mathematically. Based on this method, this paper rigorously proves that a mixture learning machine has the smaller Bayesian stochastic complexity than regular statistical models. Since the generalization error of a learning machine is equal to the increase of the stochastic complexity, the result of this paper shows that the mixture model can attain the more precise prediction than regular statistical models if Bayesian estimation is applied in statistical inference.

Bayes Theorem↗

PubMed2001

Monotherapy trials: sequential design.

In a sequential clinical trial, the accumulating data are subjected to a series of interim analyses, each of which involves a comparison of the treatments under study in respect of the primary efficacy criterion. The trial is stopped as soon as it is evident that one treatment is superior to the other, or that no such difference is going to be found. The stopping rule is devised to ensure that the required significance level and power are achieved and that valid statistical inference can be drawn at the end of the study. The methodology will be presented by means of a case study. This is the SEReNE study, which was completed last year and compared remacemide with carbamazepine in the treatment of newly diagnosed epilepsy. The study employed a double triangular test: an efficient form of sequential design for the comparison of two active treatments. The primary efficacy response was time from randomisation to the first seizure following dose titration. Details will be given of the stopping rule employed, the number of patients forecasted, the progress of the trial and its final analysis. The procedure adopted will be reviewed, and its suitability for future trials assessed.

Anticonvulsants↗

PubMed2001

Bioequivalence evaluation of lansoprazole 30-mg capsules (Lanfast and Lanzor) in healthy volunteers.

The bioequivalence of two lansoprazole 30-mg capsules was determined in healthy human, adult volunteers after a single dose in a randomized cross-over study. The study was conducted at Pharmaconsult, Flemington Pharmaceutical Corp., New Jersey, USA. Reference (Lanzor, Laboratoires Houde, Paris, France) and test (Lanfast, Julphar, UAE) were administered to volunteers with 240 ml water after overnight fasting. Blood samples were collected at specified time intervals, plasma was separated and analyzed for lansoprazole using a validated HPLC method. The pharmacokinetic parameters AUC(0-t), AUC(0-~), C(max), T(max), T(1/2) and elimination rate constant were determined from plasma concentration-time profile of both formulations and found to be in good agreement with previously reported values. The calculated pharmacokinetic parameters were compared statistically to evaluate bioequivalence between the two brands, using the statistical modules recommended by the Food and Drug Administration. The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals fell within the acceptable range (80-120%) for bioequivalence. Based on these statistical inferences it was concluded that the two formulations exhibited comparable pharmacokinetic profiles and that Julphar's Lanfast is bioequivalent to Lanzor of Lab. Houde.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed2003

Comparison of two cyclosporine formulations in healthy Middle Eastern volunteers: bioequivalence of the new Sigmasporin Microoral and Sandimmun Neoral.

A study was conducted to establish bioequivalence between two oral cyclosporine 100 mg capsules, Sigmasporin Microoral (Gulf Pharmaceutical Industries - Julphar, United Arab Emirates, under technical co-operation with Sigma Pharma, Brazil) and Sandimmun Neoral (Novartis, Switzerland), in a Middle Eastern population, even though both formulations were found to be bioequivalent earlier in a Brazilian population (data on file). It was designed as a randomized, open label, two-way crossover study in which 30 fasting, healthy male volunteers received a single 100 mg cyclosporine dose with 240 ml of water on two treatment days separated by a 1 week washout period. After dosing, serial blood samples were collected for a period of 24 h. Plasma was analyzed for cyclosporine A by a sensitive, reproducible and accurate HPLC method with MS detection capable of detecting cyclosporine A in the range of 5-400 ng/ml with a limit of quantitation of 5 ng/ml. Various pharmacokinetic parameters including AUC(0-t), AUC(0- proportional, variant ), C(max), T(max), T(1/2), and lambda(Z) were determined from plasma concentrations of both formulations. AUC(0-t), AUC(0- proportional, variant ), and C(max) were tested for bioequivalence after log-transformation of data. No significant difference was found based on ANOVA; 90% confidence intervals (82.98-110.57% for AUC(0-t), 81.57-124.71% for AUC(0- proportional, variant ), 80.15-98.91% for C(max)) for these parameters were found to be within the bioequivalence acceptance range of 80-125%. Based on these statistical inferences, it was concluded that Sigmasporin Microoral is bioequivalent to Sandimmun Neoral.

Administration, Oral↗

PubMed1998

EMG signal amplitude assessment during abdominal bracing and hollowing.

Motor pattern re-education is often used by clinicians as part of treatment regimens for chronic low back pain. Such programmes are often validated by the analysis of the electromyographical (EMG) signal from specific muscles. Independent muscles are often compared using the raw amplitude of the EMG signal or comparing the ratio of the amplitudes of two muscles. Statistical inferences from these derived data may depend on minimizing the sources of error when manipulating the EMG signal profile data. This is particularly true for amplitude normalization procedures, their reliability and the subsequent derivation of amplitude ratios. The purpose of the study was first to examine the reliability of five amplitude normalized procedures and second to examine the sensitivity of raw versus ratio amplitude comparisons during two different abdominal muscle exercises. The study demonstrated that maximal effort amplitude normalization techniques reduce the sensitivity of raw data comparisons, but had little influence on the sensitivity of the ratio data in differentiating the two movement patterns. It was concluded that using the EMG signal profile to identify pathological movement strategies, in association with regional pain syndromes, needs special attention to the reliability and validity of the derived variables.

Abdominal Muscles↗

PubMed2003

Deformation-based surface morphometry applied to gray matter deformation.

We present a unified statistical approach to deformation-based morphometry applied to the cortical surface. The cerebral cortex has the topology of a 2D highly convoluted sheet. As the brain develops over time, the cortical surface area, thickness, curvature, and total gray matter volume change. It is highly likely that such age-related surface changes are not uniform. By measuring how such surface metrics change over time, the regions of the most rapid structural changes can be localized. We avoided using surface flattening, which distorts the inherent geometry of the cortex in our analysis and it is only used in visualization. To increase the signal to noise ratio, diffusion smoothing, which generalizes Gaussian kernel smoothing to an arbitrary curved cortical surface, has been developed and applied to surface data. Afterward, statistical inference on the cortical surface will be performed via random fields theory. As an illustration, we demonstrate how this new surface-based morphometry can be applied in localizing the cortical regions of the gray matter tissue growth and loss in the brain images longitudinally collected in the group of children and adolescents.

Adolescent↗

PubMed2003

Statistical tests for fMRI based on experimental randomization.

Statistical parametric mapping (SPM) analysis of fMRI data requires specifying correctly the temporal and spatial noise covariance structure. This is a difficult if not impossible task. When these assumptions are not satisfied, statistical inference can be invalid or inefficient. Permutation tests are free of strong assumptions on the distribution of signal noise. We propose permutation tests of fMRI data based on experimental randomization of the stimulus sequences. Smooth hemodynamic response curves are estimated using quadratic B-splines. We study fMRI data obtained from event-related potential (ERP) oddball paradigm. Tests of two-tone and three-tone stimulus sequences are conducted to illustrate the application of the proposed method. Comparisons of the SPM and proposed method show that a permutation test is more specific and less susceptible to artifacts.

Arousal↗

PubMed1996

The case for better research standards in peripheral thrombolysis: poor quality of randomized trials during the past decade.

RATIONALE AND OBJECTIVES: We assessed how well published randomized controlled trials (RCTs) of peripheral thrombolysis have been designed and how they adjusted for patient characteristics that may influence responses to therapy. METHODS: RCT studies published between 1984 and 1994 were reviewed to determine whether they included nine crucial elements: sample size calculations, description of unenrolled eligible participants, homogeneous samples, balanced experimental groups, equal potency therapies, equal follow-up of outcomes, appropriate statistical inference, multivariable or subgroup analyses, and anonymous review of subjective endpoints. RESULTS: The nine RCTs complied with a median of three of nine standards (range = 2-6). Each report exhibited serious flaws that may affect generalizability and external validity. None adequately adjusted for sample heterogeneity or sought to identify characteristics that may affect responses to therapy. CONCLUSION: Failure to address prognostic or confounding variables restricts the utility of peripheral thrombolysis RCTs and helps explain why contentious debates about this therapy persist. A model for future thrombolysis trials is proposed.

Arterial Occlusive Diseases↗

PubMed2006

Robust estimation of peptide abundance ratios and rigorous scoring of their variability and bias in quantitative shotgun proteomics.

The abundance ratio between the light and heavy isotopologues of an isotopically labeled peptide can be estimated from their selected ion chromatograms. However, quantitative shotgun proteomics measurements yield selected ion chromatograms at highly variable signal-to-noise ratios for tens of thousands of peptides. This challenge calls for algorithms that not only robustly estimate the abundance ratios of different peptides but also rigorously score each abundance ratio for the expected estimation bias and variability. Scoring of the abundance ratios, much like scoring of sequence assignment for tandem mass spectra by peptide identification algorithms, enables filtering of unreliable peptide quantification and use of formal statistical inference in the subsequent protein abundance ratio estimation. In this study, a parallel paired covariance algorithm is used for robust peak detection in selected ion chromatograms. A peak profile is generated for each peptide, which is a scatterplot of ion intensities measured for the two isotopologues within their chromatographic peaks. Principal component analysis of the peak profile is proposed to estimate the peptide abundance ratio and to score the estimation with the signal-to-noise ratio of the peak profile (profile signal-to-noise ratio). We demonstrate that the profile signal-to-noise ratio is inversely correlated with the variability and bias of peptide abundance ratio estimation.

Algorithms↗

PubMed2006

Model-free deconvolution of femtosecond kinetic data.

Though shorter laser pulses can also be produced, pulses of the 100 fs range are typically used in femtosecond kinetic measurements, which are comparable to characteristic times of the studied processes, making detection of the kinetic response functions inevitably distorted by convolution with the pulses applied. A description of this convolution in terms of experiments and measurable signals is given, followed by a detailed discussion of a large number of available methods to solve the convolution equation to get the undistorted kinetic signal, without any presupposed kinetic or photophysical model of the underlying processes. A thorough numerical test of several deconvolution methods is described, and two iterative time-domain methods (Bayesian and Jansson deconvolution) along with two inverse filtering frequency-domain methods (adaptive Wiener filtering and regularization) are suggested to use for the deconvolution of experimental femtosecond kinetic data sets. Adaptation of these methods to typical kinetic curve shapes is described in detail. We find that the model-free deconvolution gives satisfactory results compared to the classical "reconvolution" method where the knowledge of the kinetic and photophysical mechanism is necessary to perform the deconvolution. In addition, a model-free deconvolution followed by a statistical inference of the parameters of a model function gives less biased results for the relevant parameters of the model than simple reconvolution. We have also analyzed real-life experimental data and found that the model-free deconvolution methods can be successfully used to get undistorted kinetic curves in that case as well. A graphical computer program to perform deconvolution via inverse filtering and additional noise filters is also provided as Supporting Information. Though deconvolution methods described here were optimized for femtosecond kinetic measurements, they can be used for any kind of convolved data where measured experimental shapes are similar.

Journal Article↗

PubMed1998

Sib mating designs for mapping quantitative trait loci.

The power to separate the variance of a quantitative trait locus (QTL) from the polygenic variance is determined by the variability of genes identical by descent (IBD) at the QTL. This variability may increase with inbreeding. Selfing, the most extreme form of inbreeding, increases the variability of the IBD value shared by siblings, and thus has a higher efficiency for QTL mapping than random mating. In self-incompatible organisms, sib mating is the closest form of inbreeding. Similar to selfing, sib mating may also increase the power of QTL detection relative to random mating. In this study, we develop an IBD-based method under sib mating designs for QTL mapping. The efficiency of sib mating is then compared with random mating. Monte Carlo simulations show that sib mating designs notably increase the power for QTL detection. When power is intermediate, the power to detect a QTL using full-sib mating is, on average, 7% higher than under random mating. In addition, the IBD-based method proposed in this paper can be used to combine data from multiple families. As a result, the estimated QTL parameters can be applied to a wide statistical inference space relating to the entire reference population.

Animals↗

PubMed2002

Parametric modeling for survival with competing risks and masked failure causes.

We consider a life testing situation in which systems are subject to failure from independent competing risks. Following a failure, immediate (stage-1) procedures are used in an attempt to reach a definitive diagnosis. If these procedures fail to result in a diagnosis, this phenomenon is called masking. Stage-2 procedures, such as failure analysis or autopsy, provide definitive diagnosis for a sample of the masked cases. We show how stage-1 and stage-2 information can be combined to provide statistical inference about (a) survival functions of the individual risks, (b) the proportions of failures associated with individual risks and (c) probability, for a specified masked case, that each of the masked competing risks is responsible for the failure. Our development is based on parametric distributional assumptions and the special case for which the failure times for the competing risks have a Weibull distribution is discussed in detail.

Carcinoma, Non-Small-Cell Lung↗

PubMed1996

Serial versus sparse sampling in toxicokinetic studies.

PURPOSE: Sparse sampling in rodent toxicokinetics usually involves the collection of a single blood sample on a given study day from each animal in a treatment group. The samples are allocated to different time points, often allowing some replicates, and statistical inferences are then made about the concentration-time behavior of the test compound. The present study compared the results of one such analysis with those obtained from serial sampling as might be applied using satellite animals. METHODS: Ten rats each received a single oral dose of tritium-labeled compound X. Blood concentrations in each rat at 10 time points post-dose were determined by liquid scintillation counting. Individual peak concentrations of blood radioactivity (Cmax) and peak times (tmax) were recorded, and area-under-curve (AUC) values were calculated by trapezoidal rule. The mean AUC and Cmax of all 10 animals over all 10 time points, referred to as AUCtrue and Cmax,true, were used as points of reference. These values were then estimated using subsets of the data that simulated satellite-animal or sparse-sampling designs. First, several different sampling schedules of 5 bleeding times were stimulated by taking subsets of the full data set. For analysis using satellite animals, serial blood concentrations from subsets of 3 or 4 rats were used to calculate point and confidence-interval estimates of AUCtrue and Cmax,true by standard methods; all possible subsets of 3 or 4 of the 10 rats were considered. For sparse data analysis, a single concentration from each of the 10 rats was used to calculate both point and confidence-interval estimates of AUCtrue by the Bailer-Satterthwaite method, and point estimates of Cmax,true, according to several different designs of replication. Animals were randomly assigned to time points, and 1000 of over 50000 possible combinations were evaluated for each bleeding schedule. The average percent absolute errors of the point estimates were computed and, for the 95% confidence intervals, average widths were determined. RESULTS: For point estimates of AUCtrue, sparse sampling yielded average percent absolute errors of 7-13%. Percent errors for 3 and 4 satellite animals were 6-12% and 5-10%, respectively. For 95% confidence intervals, sparse sampling yielded widths of 24-90% of AUCtrue, whereas for 3 and 4 satellite animals widths were 37-50% and 24-34%, respectively. For Cmax,true point estimates from sparse-sampling and satellite-animal approaches had average percent absolute errors of 5-12% and 3-8%, respectively. The confidence-interval widths for Cmax,true from the satellite-animal approach were 15-24% of Cmax,true, but coverage did not achieve the nominal 95% for some choices of sampling times. CONCLUSIONS: By using proper study designs, one can limit the number of samples and the amount of blood drawn so as not to affect the animals' health status, yet still achieve the customary pharmacokinetic objectives in a toxicity study.

Animals↗

PubMed1997

Refolding of myoglobins of nonhomologous sequences by the island model.

The folding process of sea hare myoglobin was stimulated by the island model, which does not rely on sequence homologies or statistical inference from database of known structure. Sea hare myoglobin has low sequence homology (28%), but high structural similarity, with sperm whale myoglobin, which was already simulated by the island model. Their structural similarity is shown physiochemically from the distribution of hydrophobic-residue pairs, that is, the key pairs for packing of the secondary structures. Irrelevant to the sequence homology, the secondary structures can be packed into the tertiary structure through the hydrophobic interactions among the amino acid pairs responsible for the local structure formation. The results on the two species of myoglobins indicate that, in contrast to other prediction methods, the island model is applicable to any type of protein without extra information other than the distribution of hydrophobic-residue pairs and the positions of the secondary structures. Consequently the present results provide another verification of the validity of the island model for elucidating the mechanisms of protein folding and predicting protein structures.

Amino Acid Sequence↗

PubMed2000

Factors associated with dental anxiety and attendance in middle-aged and elderly women.

The aim of this study was to analyze the association between dental anxiety, dental attendance, health status and social factors. Our previous studies have shown that dental anxiety declines with age and is associated with poor oral health. In addition, correlations between dental anxiety, dental utilization and dental status have been revealed. However, the association of these factors with general health and social factors has not been analyzed in our previous studies. In a study of women's health in Göteborg, Sweden in 1992, 1.017 urban women aged 38 to 84 years took part in a series of investigations including clinical examinations, interviews and questionnaires. In addition to descriptive and simple inference statistics, a two-part multiple logistic regression model was utilized to investigate dental anxiety and dental utilization. Dental fear was less prevalent among older women, dentate or not, although 10% of females 62 years of age and older still reported high dental anxiety (DAS > or = 12). 94% of the younger (< or = 62 yr) and 76% of the older (> or = 70 yr) women reported regular dental attendance. When separating all women into dentate and edentulous groups, 94% of the dentate and 11% of the edentulous respondents reported regular dental care. Due to the large difference in dental attendance between dentate and edentulous women, these groups were analyzed separately. Multiple logistic regression analyses showed that the following factors were associated with irregular dental utilization among dentate women: high dental anxiety, fewer teeth and restorations, more caries, poorer chewing ability and dissatisfaction with dental esthetics. In the multiple regression for dental anxiety, high fear was shown to be associated with irregular dental care, age (younger), fewer teeth, dissatisfaction with dental esthetics and lower scores on the SF-36 mental health scale. A separate analysis showed that individuals with high fear and regular, as opposed to irregular, dental attendance had more teeth at a statistically significant level, which were less often decayed and more often restored. In spite of the group with high fear and irregular attendance having fewer teeth, their level of decay was seven times higher. Overall, the results indicate a strong association between dental fear and dental attendance. Weak associations were found among socio-economic, dental health and general health factors.

Adult↗

PubMed2003

Assumptions and consequences of treating providers in therapy studies as fixed versus random effects: reply to Crits-Christoph, Tu, and Gallop (2003) and Serlin, Wampold, and Levin (2003).

In their comments on the authors' article, R. C. Serlin, B. E. Wampold, and J. R. Levin and P. Crits-Christoph, X. Tu, and R. Gallop took issue with the authors' suggestion to evaluate therapy studies with nested providers with a fixed model approach. In this rejoinder, the authors' comment on Serlin et al's critique by showing that their arguments do not apply, are based on misconceptions about the purpose and nature of statistical inference, or are based on flawed reasoning. The authors also comment on Crits-Christoph et al's critique by showing that the proposed approach is very similar to, but less inclusive than, their own suggestion.

Analysis of Variance↗

PubMed2006

Long-range polony haplotyping of individual human chromosome molecules.

We report a method for multilocus long-range haplotyping on human chromosome molecules in vitro based on the DNA polymerase colony (polony) technology. By immobilizing thousands of intact chromosome molecules within a polyacrylamide gel on a microscope slide and performing multiple amplifications from single molecules, we determined long-range haplotypes spanning a 153-Mb region of human chromosome 7 and found evidence of rare mitotic recombination events in human lymphocytes. Furthermore, the parallel nature of DNA polony technology allows efficient haplotyping on pooled DNAs from a population on one slide, with a throughput three orders of magnitudes higher than current molecular haplotyping methods. Linkage disequilibrium statistics established by our pooled DNA haplotyping method are more accurate than statistically inferred haplotypes. This haplotyping method is well suited for candidate gene-based association studies as well as for investigating the pattern of recombination in mammalian cells.

Chromosome Mapping↗