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PubMed1992

Cumulative logit modelling for ordinal response variables: applications to biomedical research.

Incorrect statistical methods are often used for the analysis of ordinal response data. Such data are frequently summarized into mean scores for comparisons, a fallacious practice because ordinal data are inherently not equidistant. The ubiquitous Pearson chi-square test is invalid because it ignores the ranking of ordinal data. Although some of the non-parametric statistical methods take into account the ordering of ordinal data, these methods do not accommodate statistical adjustment of confounding or assessment of effect modification, two overriding analytic goals in virtually all etiologic inference in biology and medicine. The cumulative logit model is eminently suitable for the analysis of ordinal response data. This multivariate method not only considers the ranked order inherent in ordinal response data, but it also allows adjustment of confounding and assessment of effect modification based on modest sample size. A non-technical account of the cumulative logit model is given and its applications are illustrated by two research examples. The SAS programs for the data analysis of the research examples are available from the author.

Anti-Bacterial Agents↗

PubMed2026

Tractor workflow: a scalable Nextflow framework for local ancestry-aware genome-wide association studies.

MOTIVATION: The routine exclusion of admixed individuals from traditional genome-wide association studies (GWAS) due to concerns about spurious associations has limited multi-ancestry genetic discovery. Tractor addresses this issue by incorporating local ancestry into association testing, enabling the identification of ancestry-enriched signals and generating ancestry-specific summary statistics. However, adoption has been constrained by the complexity of prerequisite steps, including phasing and local ancestry inference, which require substantial bioinformatics expertise and introduce key analytical decision points. RESULTS: We developed a scalable, automated Nextflow workflow that integrates phasing, local ancestry inference, and Tractor association testing into a reproducible end-to-end pipeline. To demonstrate its utility, we applied the workflow to 32 blood biomarkers in 6245 two-way African-European admixed individuals from the UK Biobank. This pipeline performed efficiently at scale, replicating known associations and uncovering key ancestry-specific loci. These associations were largely driven by variants present on African ancestral tracts but absent from European tracts, underscoring the value of local ancestry-aware methods in uncovering previously masked genetic signals. AVAILABILITY AND IMPLEMENTATION: The workflow is modular, customizable, and compatible with commonly used phasing and local ancestry tools, minimizing manual intervention while preserving analytical flexibility. By lowering technical barriers to implementation, this framework facilitates broader adoption of local ancestry-aware GWAS, paving the way for expanded genetic discovery.

Humans↗

PubMed2005

Reconstitution of ancestral green visual pigments of zebrafish and molecular mechanism of their spectral differentiation.

We previously reported that zebrafish have four tandemly duplicated green (RH2) opsin genes (RH2-1, RH2-2, RH2-3, and RH2-4). Absorption spectra vary widely among the four photopigments reconstituted with 11-cis retinal, with their peak absorption spectra (lambda(max)) being 467, 476, 488, and 505 nm, respectively. In this study, we inferred the ancestral amino acid (aa) sequences of the zebrafish RH2 opsins by likelihood-based Bayesian statistics and reconstituted the ancestral opsins by site-directed mutagenesis. The ancestral pigment (A1) to the four zebrafish RH2 pigments and that (A3) to RH2-3 and RH2-4 showed lambda(max) at 506 nm, while that (A2) to RH2-1 and RH2-2 showed a lambda(max) at 474 nm, indicating that a spectral shift had occurred toward the shorter wavelength on the evolutionary lineages A1 to A2 by 32 nm, A2 to RH2-1 by 7 nm, and A3 to RH2-3 by 18 nm. Pigment chimeras and site-directed mutagenesis revealed a large contribution (approximately 15 nm) of glutamic acid to glutamine substitution at residue 122 (E122Q) to the A1 to A2 and A3 to RH2-3 spectral shifts. However, the remaining spectral differences appeared to result from complex interactive effects of a number of aa replacements, each of which has only a minor spectral contribution (1-3 nm). The four zebrafish RH2 pigments cover nearly an entire range of lambda(max) distribution among vertebrate RH2 pigments and provide an excellent model to study spectral tuning mechanisms of RH2 in vertebrates.

Amino Acid Sequence↗

PubMed1998

A covariotide model explains apparent phylogenetic structure of oxygenic photosynthetic lineages.

The aims of the work were (1) to develop statistical tests to identify whether substitution takes place under a covariotide model in sequences used for phylogenetic inference and (2) to determine the influence of covariotide substitution on phylogenetic trees inferred for photosynthetic and other organisms. (Covariotide and covarion models are ones in which sites that are variable in some parts of the underlying tree are invariable in others and vice versa.) Two tests were developed. The first was a contingency test, and the second was an inequality test comparing the expected number of variable sites in two groups with the observed number. Application of these tests to 16S rDNA and tufA sequences from a range of nonphotosynthetic prokaryotes and oxygenic photosynthetic prokaryotes and eukaryotes suggests the occurrence of a covariotide mechanism. The degree of support for partitioning of taxa in reconstructed trees involving these organisms was determined in the presence or absence of sites showing particular substitution patterns. This analysis showed that the support for splits between (1) photosynthetic eukaryotes and prokaryotes and (2) photosynthetic and nonphotosynthetic organisms could be accounted for by patterns arising from covariotide substitution. We show that the additional problem of compositional bias in sequence data needs to be considered in the context of patterns of covariotide/covarion substitution. We argue that while covariotide or covarion substitution may give rise to phylogenetically informative patterns in sequence data, this may not always be so.

Markov Chains↗

PubMed2006

Case-control association tests correcting for population stratification.

In case-control association studies unobserved population stratification may act as a confounder, leading to an increased number of false positive results. Methods accounting for population structure by using additional genetic markers broadly follow one of two concepts: Genomic Control (GC) and Structured Association (SA). While extending existing methods of Structured Association we show that it is necessary to incorporate phenotypic information when inferring population structure, otherwise a systematic bias is introduced. Moreover, for moderate population stratification a Wald test statistic should be preferred as a Structured Association test statistic in comparison to a likelihood ratio test. The introduced extensions are compared to existing methods of Structured Association, as well as to Genomic Control, in a simulation study which is based on realistic situations of large case-control studies with moderate population stratification. A disadvantage of Genomic Control turns out to be the large variation in estimating the variance inflation factor, as well as the power loss if population structure increases. We come to the overall conclusion that Structured Association, if applied correctly, is superior to Genomic Control, at least in the case of simple population structure as simulated here.

Case-Control Studies↗

PubMed2001

Population genomics: genome-wide sampling of insect populations.

Modern population genetics underwent a major paradigm shift during the last decade of the 20th century with the discovery that thousands of genes of known function and position in a genome can be analyzed simultaneously in a single individual. The impact of this technology on insect population genetics is potentially profound. Sampling distributions of genetic statistics can now be derived from many individual loci or among many segregating sites within a gene. Inferences regarding random mating, gene flow, effective population sizes, disequilibrium, and relatedness among populations can now be based on patterns of variation at many loci. More importantly, genome-wide sampling enables population geneticists to distinguish effects that act on the whole genome from those that act on individual loci or nucleotides. We introduce the term "population genomics" to describe the process of simultaneous sampling of numerous variable loci within a genome and the inference of locus-specific effects from the sample distributions. The four critical assumptions implicit in the population genomics approach are explained in detail. Studies adopting this paradigm are reviewed, and the steps necessary to complete a population genomics study are outlined.

Animals↗

PubMed2006

GO-Diff: mining functional differentiation between EST-based transcriptomes.

BACKGROUND: Large-scale sequencing efforts produced millions of Expressed Sequence Tags (ESTs) collectively representing differentiated biochemical and functional states. Analysis of these EST libraries reveals differential gene expressions, and therefore EST data sets constitute valuable resources for comparative transcriptomics. To translate differentially expressed genes into a better understanding of the underlying biological phenomena, existing microarray analysis approaches usually involve the integration of gene expression with Gene Ontology (GO) databases to derive comparable functional profiles. However, methods are not available yet to process EST-derived transcription maps to enable GO-based global functional profiling for comparative transcriptomics in a high throughput manner. RESULTS: Here we present GO-Diff, a GO-based functional profiling approach towards high throughput EST-based gene expression analysis and comparative transcriptomics. Utilizing holistic gene expression information, the software converts EST frequencies into EST Coverage Ratios of GO Terms. The ratios are then tested for statistical significances to uncover differentially represented GO terms between the compared transcriptomes, and functional differences are thus inferred. We demonstrated the validity and the utility of this software by identifying differentially represented GO terms in three application cases: intra-species comparison; meta-analysis to test a specific hypothesis; inter-species comparison. GO-Diff findings were consistent with previous knowledge and provided new clues for further discoveries. A comprehensive test on the GO-Diff results using series of comparisons between EST libraries of human and mouse tissues showed acceptable levels of consistency: 61% for human-human; 69% for mouse-mouse; 47% for human-mouse. CONCLUSION: GO-Diff is the first software integrating EST profiles with GO knowledge databases to mine functional differentiation between biological systems, e.g. tissues of the same species or the same tissue cross species. With rapid accumulation of EST resources in the public domain and expanding sequencing effort in individual laboratories, GO-Diff is useful as a screening tool before undertaking serious expression studies.

Animals↗

PubMed2006

SIMMAP: stochastic character mapping of discrete traits on phylogenies.

BACKGROUND: Character mapping on phylogenies has played an important, if not critical role, in our understanding of molecular, morphological, and behavioral evolution. Until very recently we have relied on parsimony to infer character changes. Parsimony has a number of serious limitations that are drawbacks to our understanding. Recent statistical methods have been developed that free us from these limitations enabling us to overcome the problems of parsimony by accommodating uncertainty in evolutionary time, ancestral states, and the phylogeny. RESULTS: SIMMAP has been developed to implement stochastic character mapping that is useful to both molecular evolutionists, systematists, and bioinformaticians. Researchers can address questions about positive selection, patterns of amino acid substitution, character association, and patterns of morphological evolution. CONCLUSION: Stochastic character mapping, as implemented in the SIMMAP software, enables users to address questions that require mapping characters onto phylogenies using a probabilistic approach that does not rely on parsimony. Analyses can be performed using a fully Bayesian approach that is not reliant on considering a single topology, set of substitution model parameters, or reconstruction of ancestral states. Uncertainty in these quantities is accommodated by using MCMC samples from their respective posterior distributions.

Animals↗

PubMed2006

Comparing the predictive values of diagnostic tests: sample size and analysis for paired study designs.

BACKGROUND: Although statistical methodology is well developed for comparing diagnostic tests in terms of their sensitivities and specificities, comparative inference about predictive values is not. PURPOSE: In this paper we consider the design and analysis of studies comparing the positive and negative predictive values of two diagnostic tests that are measured on all subjects. METHODS: We focus on comparing tests using the relative positive and negative predictive values. We discuss directly estimating these quantities from the data and derive analytic variance expressions. Sample size formulas for study design ensue. RESULTS: We analyze data on patients with cystic fibrosis to illustrate the methodology. This approach is compared and contrasted with an existing regression framework that can also be used for similar analysis purposes and yields similar results. CONCLUSIONS: We have developed a new approach for comparing the predictive values of two tests that gives rise to sample size formulas for study design.

Biometry↗

PubMed2002

Intensive direct cavernous sinus sampling identifies high-frequency, nearly random patterns of FSH secretion in ovariectomized ewes: combined appraisal by RIA and bioassay.

Analyses of FSH secretion suggest pulsatile, nonpulsatile, or compositely pulsatile and nonpulsatile release modes. This may reflect the reduced signal-to-noise ratio inherent in FSH pulse estimation procedures and/or immunological-biological assay inconsistencies. To address these issues, we sampled cavernous sinus and jugular venous blood concomitantly from ovariectomized sheep at either 5-min or 1-min intervals. Samples from the former were assayed by RIA, and those from the latter by RIA and bioassay. Waveform-independent peak detection revealed FSH pulses occurring at high frequency. Pulsatile FSH secretion accounted for 28% of total secretion. Approximate entropy analysis showed that FSH secretion was nearly random. There was synchronous release of LH and FSH, but most FSH secretion was not associated with LH release; 13% of discrete FSH and LH pulses were concordant. We infer that FSH secretion exhibits pulsatile and basal/nonpulsatile features, with high-entropy features. Linear and nonlinear statistical measures revealed joint sample-by-sample synchrony of FSH and LH release, indicating pattern coordination despite sparse synchrony of pulses. We postulate that pattern synchrony of FSH and LH release is effected at the level of the gonadotrope. Concordant FSH and LH pulses probably result from pulsatile GnRH input, but other mechanisms could account for independent FSH pulses.

Animals↗

PubMed1994

Alcohol outlet density and motor vehicle crashes in Los Angeles County cities.

The extent to which the availability of alcohol encourages alcohol consumption resulting in alcohol-related problems remains controversial. In order to address this issue we used 1990 data from 72 cities within Los Angeles County to estimate the relation between densities of four types of alcohol outlets (restaurants, bars, liquor stores, mini-markets) and rates of two types of alcohol-related motor vehicle crashes reported by police (injury, property damage). After logarithmic transformation of variables, crash rates were regressed on outlet densities and possible demographic confounders. The demographic covariates accounted for 25% of the variance in injury crashes; adding the combined outlet density to the model yielded a significant elasticity estimate (beta +/- SE) (beta = 0.55 +/- 0.13). Separate models for types of outlets yielded significant elasticities for restaurants (beta = 0.22 +/- 0.07), liquor stores (beta = 0.46 +/- 0.17) and mini-markets (beta = 0.34 +/- 0.13), but not for bars (beta = 0.08 +/- 0.07). Alcohol-related crashes resulting in property damage also showed positive associations with outlet densities, but these associations were smaller and reached statistical significance for restaurants (beta = 0.19 +/- 0.11) and bars (beta = 0.21 +/- 0.10). Direction of influence cannot be inferred from these cross-sectional findings, but they do indicate that increased alcohol availability is geographically associated with increased alcohol-related motor vehicle crashes and that this association is independent of measured confounders.

Accidents, Traffic↗

PubMed1998

[Exploration on statistical method for calculating intensity of the infection in residents in nationwide sampling survey of schistosomiasis].

AIM: To set up statistical methods for calculation of intensity of schistosome infection in residents in nationwide sampling survey of schistosomiasis. METHODS: Based on the epidemiological survey of schistosomiasis and according to the medical statistics for multiple stratifying and clustering random sampling, the calculation method on intensity of schistosome infection was inferred. RESULTS AND CONCLUSION: Nine formulas were worked out for the calculation of the intensity of schistosome infection in different endemic provinces with different ecotypes. These formulas are of practical value.

China↗

PubMed1988

Contribution of serum level monitoring in the individualization of carbamazepine dosage regimens.

The aim of the present work was to assess the forecasting efficiency of methods of dosage individualization for carbamazepine according to mean population pharmacokinetic parameters (method 1) and from information relating to one (method 2) or more (method 3) measured steady-state serum drug levels in 344 epileptic patients. All the individuals studied were outpatients on a multiple dosage regimen with carbamazepine. Carbamazepine serum levels were analyzed by an enzyme multiplied immunoassay technique (EMIT). The accuracy and precision of methods 1, 2 and 3 were judged by the mean prediction error (m.e.) and the root mean squared error (m.s.e.) that had values of -1.1 +/- 3.5 and 2.8 +/- 2.3; 0.3 +/- 2.0 and 1.4 +/- 1.5 and -0.15 +/- 1.9 and 1.4 +/- 1.2 for methods 1, 2 and 3, respectively. From the statistical analysis of the experimental data and those predicted by the three methods studied, it may be inferred that the availability of data referring to the drug serum levels contributes decisively to the establishment of a correct dosage regimen.

Adolescent↗

PubMed1986

Inference based on type II censored samples.

A method for drawing inferences about the mean of a normal population from small censored samples is discussed. The modified standardized statistic presented takes into account the correlation between the estimates of the mean and standard deviation and thus gives asymmetrical confidence intervals in contrast to the common standardized variate. A bias correction is suggested which improves the performance of the proposed statistic for small samples.

Biometry↗

PubMedDate not supplied

Automatic detection of acute bacterial pneumonia from chest X-ray reports.

OBJECTIVE: To evaluate the performance of a natural language processing system in extracting pneumonia-related concepts from chest x-ray reports. METHODS DESIGN: Four physicians, three lay persons, a natural language processing system, and two keyword searches (designated AAKS and KS) detected the presence or absence of three pneumonia-related concepts and inferred the presence or absence of acute bacterial pneumonia from 292 chest x-ray reports. Gold standard: Majority vote of three independent physicians. Reliability of the gold standard was measured. OUTCOME MEASURES: Recall, precision, specificity, and agreement (using Finn's R: statistic) with respect to the gold standard. Differences between the physicians and the other subjects were tested using the McNemar test for each pneumonia concept and for the disease inference of acute bacterial pneumonia. RESULTS: Reliability of the reference standard ranged from 0.86 to 0.96. Recall, precision, specificity, and agreement (Finn R:) for the inference on acute bacterial pneumonia were, respectively, 0.94, 0.87, 0.91, and 0.84 for physicians; 0.95, 0.78, 0.85, and 0.75 for natural language processing system; 0.46, 0.89, 0.95, and 0.54 for lay persons; 0.79, 0.63, 0.71, and 0.49 for AAKS; and 0.87, 0.70, 0.77, and 0.62 for KS. The McNemar pairwise comparisons showed differences between one physician and the natural language processing system for the infiltrate concept and between another physician and the natural language processing system for the inference on acute bacterial pneumonia. The comparisons also showed that most physicians were significantly different from the other subjects in all pneumonia concepts and the disease inference. CONCLUSION: In extracting pneumonia related concepts from chest x-ray reports, the performance of the natural language processing system was similar to that of physicians and better than that of lay persons and keyword searches. The encoded pneumonia information has the potential to support several pneumonia-related applications used in our institution. The applications include a decision support system called the antibiotic assistant, a computerized clinical protocol for pneumonia, and a quality assurance application in the radiology department.

Acute Disease↗

PubMed1990

The use of historical data for identifying biologically unimportant but statistically significant results in genotoxicity assays.

The definition of a negative result is a problem in genetic toxicology. Here we suggest that a result may be considered biologically unimportant (negative) if it falls within the limits of variation usually found in the negative controls of the particular test. To determine 'usual' variation, we have set 95% confidence limits on three indices of variation, calculated from historical values for duplicate negative control data from several genotoxicity tests. These tests showed four characteristic types of response and the appropriate index of variability was determined for each. Where there was little test-to-test variation in true mean (micronucleus test and metaphase analysis), confidence limits set on the overall distribution of negative controls were the best index of variability. In other assays (Ames, yeast and mouse lymphoma), there was considerable test-to-test variation so that differences between, or ratios of, the members of control duplicates were the preferred measure of variability. This approach can define what is biologically unimportant in terms of the test system. However, no inference can be drawn as to potential importance. Thus the main use is the removal of the positive 'label' from statistically significant results which fall within the usual range of spontaneous variation for the assay under consideration.

Animals↗

PubMed2005

Species status and phylogeography of two closely related Coptolabrus species (Coleoptera: Carabidae) in South Korea inferred from mitochondrial and nuclear gene sequences.

We investigated the species status and intraspecific phylogeography in South Korea of two ground beetle species, Coptolabrus jankowskii and Coptolabrus smaragdinus (Coleoptera: Carabidae), using statistical parsimony networks and nested clade analyses based on sequences from the mitochondrial cytochrome oxidase subunit I (COI) and nuclear phosphoenolpyruvate carboxykinase (PepCK) and wingless (Wg) genes. Although traditional parsimony tree construction generally failed to resolve interspecific relationships and construct biologically meaningful genealogies, analysis using statistical parsimony networks yielded statistically significant inter- and intraspecific genealogical structures. We found that although these two species represent a notable case of trans-species polymorphisms in both mitochondrial and nuclear gene sequences, their status as separate species was evidenced by the nonrandom association between species and nested clades at various nesting levels. The exceptional occurrence of shared identical or very similar COI sequences was considered to be the result of introgressive hybridization. In addition, range expansion and fragmentation events across the Korean Peninsula and adjacent islands were inferred from nested clade phylogeographical analyses. The COI gene revealed the geographical divergence of major eastern and western clades and historical biogeographical events within each major clade, whereas the nuclear PepCK gene, which did not reveal corresponding east-west clades, indicated past fragmentation and range expansion across wide areas that may have been the result of older biogeographical events. Thus, phylogeographical inferences drawn from analyses of mitochondrial and nuclear genes can reveal different and potentially complementary information about phylogeographical processes.

Animals↗

PubMedDate not supplied

Controlled trial of aspirin in cerebral ischemia.

Adouble-blind trial of aspirin for the treatment of cerebral ischemia was begun in 1972 and continued for 37 months. This was accomplished despite difficulties in controlling a long-term study of a drug which has widespread availability and consumption. The study design, criteria for selection of patients, follow-up surveillance, and methods of data analysis are presented. We report only subjects without carotid surgery before randomization. Patients (178) who had carotid transient ischemic attacks (TIAs) were randomly allocated to aspirin or placebo and followed to determine the incidence of subsequent TIAs,death, cerebral infarction or retinal infarction. Analysis of the first six months of follow-up revealed a statistically significant differential in favar of aspirin when death or cerebral or retinal infarction and the occurrence of TIAs were grouped and considered together as end points. Significance in favor of aspirin treatment was mainly revealed in patients with a history of multiple TIAs and was most evident in those individuals having carotid lesions appropriate to the TIA symptoms. It cannot be inferred from this study that aspirin prevents stroke because when end points were restriced to death or cerebral or retinal infarction, there was no statistically significant differential between the aspirin and placebo treatments.

Aged↗