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PubMed2006

Multivariate statistical tools applied to the characterization of the proteomic profiles of two human lymphoma cell lines by two-dimensional gel electrophoresis.

Mantle cell lymphoma (MCL) cell lines have been difficult to generate, since only few have been described so far and even fewer have been thoroughly characterized. Among them, there is only one cell line, called GRANTA-519, which is well established and universally adopted for most lymphoma studies. We succeeded in establishing a new MCL cell line, called MAVER-1, from a leukemic MCL, and performed a thorough phenotypical, cytogenetical and molecular characterization of the cell line. In the present report, the phenotypic expression of GRANTA-519 and MAVER-1 cell lines has been compared and evaluated by a proteomic approach, exploiting 2-D map analysis. By univariate statistical analysis (Student's t-test, as commonly used in most commercial software packages), most of the protein spots were found to be identical between the two cell lines. Thirty spots were found to be unique for the GRANTA-519, whereas another 11 polypeptides appeared to be expressed only by the MAVER-1 cell line. A number of these spots could be identified by MS. These data were confirmed and expanded by multivariate statistical tools (principal component analysis and soft-independent model of class analogy) that allowed identification of a larger number of differently expressed spots. Multivariate statistical tools have the advantage of reducing the risk of false positives and of identifying spots that are significantly altered in terms of correlated expression rather than absolute expression values. It is thus suggested that, in future work in differential proteomic profiling, both univariate and multivariate statistical tools should be adopted.

Cell Line, Tumor↗

PubMed1995

Statistical design and analysis of mutation studies in transgenic mice.

We have been working on identifying sources of variability in data from transgenic mouse mutation assays in order to develop appropriate statistical methods and designs for routine studies. Data from our lab and elsewhere point to the presence of significant animal-to-animal variability, which must be taken into account in statistical hypothesis tests. Here, the usual Cochran-Armitage (CA) test for trend in mutant frequencies, which takes the transgene as the experimental unit, and a generalized Cochran-Armitage test (GCA), which takes the animal as the experimental unit, are contrasted in computer simulations that help to quantify the differences between these statistical tests. The simulations report the statistical power of each test to detect treatment group differences, and their type I error rates. We find in general that the GCA test performs poorly compared to the CA test when it is appropriate to take the transgene as the experimental unit, and the study also uses a small number of animals. However, the CA test performs poorly in small group-size studies when the animal is the appropriate experimental unit. Extensions of the computer simulations allow for identification of cost-effective experimental designs. The results emphasize that the benefits of using additional animals in these mutation studies can be realized without substantial increases in costs. Here we illustrate the methods for liver studies in our lab. These methods can be used to derive optimal experimental designs for any combination of spontaneous mutant frequency and animal-to-animal variability.

Animals↗

PubMed1989

Statistical properties of the haplotype relative risk.

In the haplotype relative risk (HRR) statistic (Rubinstein et al.: Human Immunol 3:384 [abstract], 1981), a disease sample is constructed along with its own internal control by comparing those marker alleles passed from the parents to an affected child with the other parental marker alleles not transmitted. Based on the conditional parental genotype distribution given that they have an affected child, statistical properties of the HRR statistic are derived. It is shown that the HRR is different from 1 only when allelic association is present and the recombination fraction is different from 1/2. Transmitted and nontransmitted marker alleles are shown to be statistically independent only in the absence of either allelic association or recombination.

Genetic Diseases, Inborn↗

PubMed2001

A robust multipoint linkage statistic (tlod) for mapping complex trait loci.

Classical parametric two-point linkage analysis is a powerful analysis tool, however there are clear disadvantages too, including the sensitivity to allele frequency mis-specification. Conversely, multipoint linkage analysis is not sensitive to allele frequency mis-specification, but it is sensitive to genetic model mis-specification. Göring and Terwilliger [Am J Hum Genet 66:1095-106, 2000] proposed a new robust multipoint statistic that increased the robustness of multipoint analyses. In this paper we have referred to this new statistic as the tlod. We applied this new statistic to the Genetic Analysis Workshop (GAW) 12 data using affected status (AFF) as the phenotype of interest. The heterogeneity tlod and two-point hlod scores correlated highly across the genome (p < 0.0001), as expected, but the het-tlod had a lower number false positives. In addition, the tlod analysis handled missing data better, as would be expected for a multipoint method. When one-third of the genotype data was removed (dead people) the tlod analysis was less affected than the two-point analysis. When tlod scores were compared with multipoint lod scores in true gene locations, the robustness of the tlod to model mis-specification was clearly evident. When the "best" replicate from the general population was analyzed, a borderline genome-wide significant two-point hlod result (3.6) was found 4 cM from MG6 and MG7 on chromosome 6. The heterogeneity tlod score was lower than the two-point hlod score (1.8), but greater than the heterogeneity multipoint lod score (0.4). However, when replicate 1 of the isolated population was analyzed none of the true gene locations were identified with either statistic.

Chromosome Mapping↗

PubMed1993

Cross-validation of protein structural class prediction using statistical clustering and neural networks.

We present an approach to predicting protein structural class that uses amino acid composition and hydrophobic pattern frequency information as input to two types of neural networks: (1) a three-layer back-propagation network and (2) a learning vector quantization network. The results of these methods are compared to those obtained from a modified Euclidean statistical clustering algorithm. The protein sequence data used to drive these algorithms consist of the normalized frequency of up to 20 amino acid types and six hydrophobic amino acid patterns. From these frequency values the structural class predictions for each protein (all-alpha, all-beta, or alpha-beta classes) are derived. Examples consisting of 64 previously classified proteins were randomly divided into multiple training (56 proteins) and test (8 proteins) sets. The best performing algorithm on the test sets was the learning vector quantization network using 17 inputs, obtaining a prediction accuracy of 80.2%. The Matthews correlation coefficients are statistically significant for all algorithms and all structural classes. The differences between algorithms are in general not statistically significant. These results show that information exists in protein primary sequences that is easily obtainable and useful for the prediction of protein structural class by neural networks as well as by standard statistical clustering algorithms.

Algorithms↗

PubMed2002

Likelihood methods for measuring statistical evidence.

Focused on interpreting data as statistical evidence, the evidential paradigm uses likelihood ratios to measure the strength of statistical evidence. Under this paradigm, re-examination of accumulating evidence is encouraged because (i) the likelihood ratio, unlike a p-value, is unaffected by the number of examinations and (ii) the probability of observing strong misleading evidence is naturally low, even for study designs that re-examine the data with each new observation. Further, the controllable probabilities of observing misleading and weak evidence provide assurance that the study design is reliable without affecting the strength of statistical evidence in the data. This paper illustrates the ideas and methods associated with using likelihood ratios to measure statistical evidence. It contains a comprehensive introduction to the evidential paradigm, including an overview of how to quantify the probability of observing misleading evidence for various study designs. The University Group Diabetes Program (UGDP), a classic and still controversial multi-centred clinical trial, is used as an illustrative example. Some of the original UGDP results, and subsequent re-analyses, are presented for comparison purposes.

Biometry↗

PubMedDate not supplied

What do doctors know about statistics?

A multiple choice test with nine statistical questions was sent to a random sample of Danish doctors to assess their knowledge of elementary statistical expressions (SD, SE, p less than 0.05, p greater than 0.05 and r). One hundred and forty eight (59 per cent) of 250 doctors answered the questions. The test was also completed by 97 participants in postgraduate courses in research methods, mainly junior hospital doctors. The median number of correct answers was 2.4 in the random sample and 4.0 in the other sample of doctors. It is concluded that the statistical knowledge of most doctors is so limited that they cannot be expected to draw the right conclusions from those statistical analyses which are found in papers in medical journals. Sixty-five per cent of the doctors in the random sample stated that it is very important that this problem is raised.

Biometry↗

PubMed1993

Interfacing U.S. census map files with statistical graphics software: application and use in epidemiology.

In 1990, the United States Bureau of the Census released detailed geographic map files known as TIGER/Line (Topologically Integrated Geographic Encoding and Referencing). The TIGER files, accessible through purchase or federal repository libraries, contain 24 billion characters of data describing various geographic features including coastlines, hydrography, transportation networks, political boundaries, etc. for the entire United States. Many of these physical features are of potential interest in epidemiological case studies. Unfortunately, the TIGER data base only provides raw alphanumeric data; no utility software, graphical or otherwise, is included. Recently, the S statistical software package has been extended to include a map display function. The map function augments S's high-level approach towards statistical analysis and graphical display of data. Coupling this statistical software with the map data base developed for U.S. Census data collection will facilitate epidemiological research. We discuss the technical background necessary to utilize the TIGER data base for mapping with S. Two types of S maps, segment-based and polygon-based, are discussed along with methods to construct them from TIGER data. Polygon-based maps are useful for displaying regional statistical data, such as disease rates or incidence at the census tract level. Segment-based maps are easier to assemble and are appropriate when the data are not regionalized. Census tract data of AIDS incidence in San Francisco and lung cancer case locations relative to petrochemical refinery sites in Contra Costa County are used to illustrate the methods and potential uses of interfacing the TIGER data base with S.

Acquired Immunodeficiency Syndrome↗

PubMed1998

Formal representation of summary tables for health care statistical database management.

There is an ever-increasing demand for statistical information in health-care societies, and voluminous statistics are collected every year. When one needs information on survey results, it is generally not allowed to access the original data, and the summary tables are the most important source of information which can be shared. In order to store summary tables as a well-organized database and to perform flexible retrieval, a formal study has been made on the structure of summary tables. We introduce the notion of summary table scheme and define the operations called table transformation. A statistical database management system has been implemented based on the study. In our study, a statistical database is a collection of summary tables obtained from a survey. If a survey is conducted periodically, a database consists of all the tables obtained in the past. System utilities have been implemented for handling time-oriented information.

Algorithms↗

PubMed1996

Statistical potentials extracted from protein structures: how accurate are they?

"Statistical potentials" are energies widely used in computer algorithms to fold, dock, or recognize protein structures. They are derived from: (1) observed pairing frequencies of the 20 amino acids in databases of known protein structures, and (2) approximations and assumptions about the physical process that these quantities measure. Using exact lattice models, we construct a rigorous test of those assumptions and approximations. We find that statistical potentials often correctly rank-order the relative strengths of interresidue interactions, but they do not reflect the true underlying energies because of systematic errors arising from the neglect of excluded volume in proteins. We find that complex residue-residue distance dependences observed in statistical potentials, even those among charged groups, can be largely explained as an indirect consequence of the burial of non-polar groups. Our results suggest that current statistical potentials may have limited value in protein folding algorithms and wherever they are used to provide energy-like quantities.

Algorithms↗

PubMed1998

Empirical statistical estimates for sequence similarity searches.

The FASTA package of sequence comparison programs has been modified to provide accurate statistical estimates for local sequence similarity scores with gaps. These estimates are derived using the extreme value distribution from the mean and variance of the local similarity scores of unrelated sequences after the scores have been corrected for the expected effect of library sequence length. This approach allows accurate estimates to be calculated for both FASTA and Smith-Waterman similarity scores for protein/protein, DNA/DNA, and protein/translated-DNA comparisons. The accuracy of the statistical estimates is summarized for 54 protein families using FASTA and Smith-Waterman scores. Probability estimates calculated from the distribution of similarity scores are generally conservative, as are probabilities calculated using the Altschul-Gish lambda, kappa, and eta parameters. The performance of several alternative methods for correcting similarity scores for library-sequence length was evaluated using 54 protein superfamilies from the PIR39 database and 110 protein families from the Prosite/SwissProt rel. 34 database. Both regression-scaled and Altschul-Gish scaled scores perform significantly better than unscaled Smith-Waterman or FASTA similarity scores. When the Prosite/ SwissProt test set is used, regression-scaled scores perform slightly better; when the PIR database is used, Altschul-Gish scaled scores perform best. Thus, length-corrected similarity scores improve the sensitivity of database searches. Statistical parameters that are derived from the distribution of similarity scores from the thousands of unrelated sequences typically encountered in a database search provide accurate estimates of statistical significance that can be used to infer sequence homology.

Animals↗

PubMed2000

A Bayesian statistical method for the detection and quantification of rotational diffusion anisotropy from NMR relaxation data.

It has recently become more widely appreciated that the presence of rotational diffusional anisotropy in proteins and other macromolecules can have a significant affect on the interpretation of NMR relaxation data in terms of molecular motion. In this paper, we show how commonly used NMR relaxation data (R(1), R(2), and NOE) obtained at two spectrometer frequencies can be analyzed using a Bayesian statistical approach to reliably detect and quantify the degree of rotational diffusion anisotropy. Our approach differs from previous methods in that it does not make assumptions concerning the internal motions experienced by the residues which are used to quantify the diffusion anisotropy, but rather averages the results over all internal motions consistent with the data. We demonstrate our method using synthetic data corresponding to isotropic, axially symmetric anisotropic, and fully asymmetric anisotropic rotational diffusion, as well as experimental NMR data. We compare the Bayesian statistical approach with a widely used method for extracting tumbling parameters using both synthetic and experimental data. While it can be difficult to separate the effects of chemical exchange from rotational anisotropy using this "standard" method, these effects are readily separated using Bayesian statistics. In addition, we find that the Bayesian statistical approach requires considerably less CPU time than an equivalent standard analysis.

Algorithms↗

PubMed1977

[Age, duration of disease and survival period of patients with involvement of the nervous system by malignant lymphomas. A statistical comparison of mycosis fungoides with lymphogranulomatosis (author's transl)].

A statistical comparison dealing with age, duration of disease and survival period of patients with involvement of the nervous system by malignant lymphomas revealed the following data: 1. With mycosis fungoides, involvement of the nervous system occurs later in life than with lymphogranulomatosis; this difference is statistically highly significant (P less than 0.001). 2. There is no statistical difference (P greater than 0.05) in the duration of either type of malignant lymphoma before the nervous system becomes involved. 3. It is of high statistical significance (P less than 0.001) that, once the nervous system has become involved, the survival period is lower with mycosis fungoides than with lymphogranulomatosis. It can be expected that involvement of the nervous system by mycosis fungoides leads with 79% probability (confidential limits 99% = 47.29--96.22%) to death within 6 months.

Age Factors↗

PubMed1976

[Statistical analysis of congenital hip dysplasia is not possible in the first months of life! (author's transl)].

The question whether congenital hip dysplasia can be defined statistically has been raised again by Kristen, Dorda and Zweymüller. These authors believe that a definition is possible by statistical methods. Compiling a normal material for statistical evaluation, however, needs a clinical separation of normal and dysplastic joints before. And this--in our opinion--is not possible during the first half year of life. The only possible way is a long-term follow-up. In our own investigation children with higher acetabular indices have been followed up to 5 years and more. Only by this clinical evaluation is it possible to say which joints have developed normally and which have not. This is a clinical diagnosis of hip dysplasia, not a statistical.

Age Factors↗

PubMed1985

The design and structure of clinical research information systems. Implications for data retrieval and statistical analyses.

Data management software designed to support clinical data bases typically provides the user with the ability to "enter" and "retrieve" information according to simple user-specified criteria. In the medical research environment, such data base management systems can be self-limiting unless the user has carefully structured the data base schema to be consistent with subsequent statistical procedures used for analysis. For statistical purposes, the data base schema must be configured such that the dependent and independent variables are structurally situated to facilitate the use of statistical application programs. Furthermore, the analysis of time-oriented, prospective studies often requires the data base to be "relational." This may be inconsistent with data collection procedures that result in "hierarchical" schemata. Methodology for ensuring compatibility between the data base schema and subsequent statistical analyses is presented using examples derived from a multicenter clinical trial of diabetes and an observational data bank approach to disease surveillance in rheumatology.

Computers↗

PubMed1990

Digital ambulatory manometry of the small intestine in healthy adults. Estimates of variation within and between individuals and statistical management of incomplete MMC periods.

A new technique for ambulatory manometry of the small intestine with digital storage of signals is presented. Postprandial motility after a 1700-kJ meal and nighttime fasting motility were recorded in 19 healthy young adults. A comprehensive statistical approach was worked out to illuminate the statistical properties of fasting motility data from long-term studies. Separate quantifications of the variation within and between individuals are presented for the migrating motor complex (MMC). The overall mean for the MMC period was 107 min, with incomplete periods included as censored data. Standard deviation within individuals was 49 min, and standard deviation between individuals 16 min. Presented in the same manner, phase III in the proximal jejunum lasted 5.3 min, with standard deviations of 1.5 and 1.1 min, respectively. The propagation velocity of phase III in the distal duodenum was 10.8 cm/min, with standard deviations of 3.7 and 4.1 cm/min, respectively. Fed-state lasted 324 +/- 110 min (mean +/- SD), and adjusted fed-state, an alternative definition proposed in this study, 290 +/- 80 min. This variance component model, extended to handle censored data, provides a useful statistical approach for the analyses of the MMC. The MMC period proved to be less suitable for quantitative comparisons because of dominating intraindividual variance. Comparisons presented indicate that discrepancies in reference values depend, to a great extent, on the statistical methods applied.

Adult↗

PubMed1986

Statistical properties of molecular tree construction methods under the neutral mutation model.

The statistical properties of three molecular tree construction methods--the unweighted pair-group arithmetic average clustering (UPG), Farris, and modified Farris methods--are examined under the neutral mutation model of evolution. The methods are compared for accuracy in construction of the topology and estimation of the branch lengths, using statistics of these two aspects. The distribution of the statistic concerning topological construction is shown to be as important as its mean and variance for the comparison. Of the three methods, the UPG method constructs the tree topology with the least variation. The modified Farris method, however, gives the best performance when the two aspects are considered simultaneously. It is also shown that a topology based on two genes is much more accurate than that based on one gene. There is a tendency to accept published molecular trees, but uncritical acceptance may lead one to spurious conclusions. It should always be kept in mind that a tree is a statistical result that is affected strongly by the stochastic error of nucleotide substitution and the error intrinsic to the tree construction method itself.

Biological Evolution↗

PubMed2006

Statistical methods of estimating fracture risk.

The aim of the article is to present an analysis of statistical methods used for estimating fracture risk in patients with osteoporosis. Mathematical relations of different methods are explained (risk--R, risk ratio--RR, RD--risk difference, odds--O, odds ratio--OR, Yule's Q, Yule's Y, logistic model). What is important to keep in mind is that: 1) relative risk and odds ratio are statistics that only describe an association, not causation; 2) relative risk and odds ratio refer to a population, not to an individual patient; 3) the studies of small groups are more likely to find an association that might actually just be due to chance, the larger the groups, the less likely the association between a risk factor and an outcome (fracture); 4) when the incidence of an outcome of interest in the study population is low (<10 %), the OR is close to the RR, the more frequent the outcome becomes, the more the OR will overestimate the RR when it is more than 1 or underestimate the RR when it is less than 1. Sophisticated statistical packages are available which can calculate many of the tests of association but the problem is that the investigator must know which is the desirable one. The incorrect option of statistical analysis, the incorrect interpretation of risk ratio or odds ratio and overestimation of the importance of a risk factor may lead to unintentional errors in the economic analysis of potential programs or treatments in osteoporosis. This article could be a contribution for investigators who are concerned with assessment of fracture risk.

Age Factors↗