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PubMed2003

Bayesian analysis of structural equation models with dichotomous variables.

Structural equation modelling has been used extensively in the behavioural and social sciences for studying interrelationships among manifest and latent variables. Recently, its uses have been well recognized in medical research. This paper introduces a Bayesian approach to analysing general structural equation models with dichotomous variables. In the posterior analysis, the observed dichotomous data are augmented with the hypothetical missing values, which involve the latent variables in the model and the unobserved continuous measurements underlying the dichotomous data. An algorithm based on the Gibbs sampler is developed for drawing the parameters values and the hypothetical missing values from the joint posterior distributions. Useful statistics, such as the Bayesian estimates and their standard error estimates, and the highest posterior density intervals, can be obtained from the simulated observations. A posterior predictive p-value is used to test the goodness-of-fit of the posited model. The methodology is applied to a study of hypertensive patient non-adherence to medication.

Algorithms↗
PubMed2003

A hierarchical model for spatially clustered disease rates.

Maps of regional disease rates are potentially useful tools in examining spatial patterns of disease and for identifying clusters. Bayes and empirical Bayes approaches to this problem have proven useful in smoothing crude maps of disease rates. In recent years, models including both spatially correlated random effects and spatially unstructured random effects have been very popular. The spatially correlated random effects have been proposed in an attempt to capture a general clustering in the data. As an alternative, we propose replacing the spatially structured random effect with fixed clustering effects associated with particular areas. A reversible jump Markov chain Monte Carlo (RJMCMC) algorithm for posterior inference is described. We illustrate the model using the well-known New York leukaemia data.

Cluster Analysis↗
PubMedDate not supplied

A distribution-free test for paired growth curve analyses with application to an animal tumour immunotherapy experiment.

We describe distribution-free statistical methodology for assessing the equivalence of paired growth curves. This procedure may be used with incomplete observations, and in situations where parametric models for growth are inappropriate. We present data from an experiment investigating an immunotherapy regimen in a murine tumour system and which we have analysed with this technique.

Animals↗
PubMed1994

Precision of incidence predictions based on Poisson distributed observations.

Disease incidence predictions are useful for a number of administrative and scientific purposes. The simplest ones are made using trend extrapolation, on either an arithmetic or a logarithmic scale. This paper shows how approximate confidence prediction intervals can be calculated for such predictions, both for the total number of cases and for the age-adjusted incidence rates, by assuming Poisson distribution of the age and period specific numbers of incident cases. Generalizations for prediction models, for example, using power families and extra-Poisson variation, are also presented. Cancer incidence predictions for the Stockholm-Gotland Oncological Region in Sweden are used as an example.

Adult↗
PubMedDate not supplied

Dependent HIV incidences in back-projection of AIDS incidence data.

Techniques for reconstructing plausible HIV incidence curves from AIDS incidence data are called methods of back-projection, or back-calculation. Approaches to back-projection tend to make the simplifying assumption that the quarterly HIV incidences are independent, which is not even approximately true. Here we investigate whether smoothed non-parametric back-projection based on this simplifying assumption gives sensible back-projections and appropriate measures of precision for these reconstructed HIV incidence curves. Simple models for HIV transmission are shown to have much greater variation than the corresponding non-homogeneous Poisson process arising from the independence assumption. Nevertheless, bearing in mind that the objective is to reconstruct the HIV epidemic curve for the current epidemic, it is argued that such back-projection does give sensible HIV curves. This conclusion is supported by a simulation study, which also finds that confidence intervals for the HIV incidences are wider for transmission data than those determined from independent Poisson data.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Codon-based combinatorial alanine scanning site-directed mutagenesis: design, implementation, and polymerase chain reaction screening.

Combinatorial alanine scanning mutagenesis is a powerful tool for the exploration of protein structure-function relationships. Unfortunately, combinatorial alanine replacement of multiple residues using standard site-directed mutagenesis is restricted to a subset of amino acids. To circumvent this limitation, an efficient procedure for combinatorial site-specific replacement by alanine of any residue in a given protein sequence has been established. The method, which involves simple procedures and commonly used materials, is based upon the use of codon-based mutagenesis. A defined ratio of alanine to wild-type codon was introduced at each predetermined triplet using the "column-splitting" technique during oligonucleotide synthesis. High-throughout genetic screening of mutant libraries was facilitated by the incorporation of diagnostic restriction sites at targeted codons followed by a PCR-based screening procedure. The method was tested on a set of 13 residues located at the interface between the variable domains of a Fab fragment of an antibody. The occurrence of alanine substitution was found to be comparable to the statistically predicted distribution.

Alanine↗
PubMed1993

Nervous system effects of occupational exposure to styrene: a clinical and neurophysiological study.

Quantitative EEG of 99 workers occupationally exposed to styrene was analyzed and compared to exposure parameters. All of the workers came from reinforced plastics industry. The workplaces and factories were previously evaluated, and the exposure levels were known rather accurately. The exposure information form workplaces and the individual exposure data were combined to form an Exposure Index, which reliably reflected long-term exposure to styrene in various occupational settings. All of the subjects underwent careful medical, neurological, and neurophysiological examinations. Quantitative EEG was recorded from 19 channels and analyzed for absolute and relative power, asymmetry, coherence, frequency distribution, and statistical normative database comparisons (Neurometrics). The EEG data showed a significant increase of abnormal EEG classifications in workers with higher exposure. When the workers were divided into two groups, based on the exposure data, those with higher exposure had higher absolute EEG power in alpha and beta bands in the frontotemporal regions of the brain. The findings indicate that abnormalities in cerebral function can be demonstrated even with relatively low mean exposure levels. It is concluded that the efforts to lower the administrative hygienic levels of styrene have been in the right direction.

Adult↗
PubMed2001

The lead content of blood serum.

Serum lead concentrations measured by stable isotope dilution with a thermal ionization mass spectrometer and blood lead concentrations measured by graphite furnace atomic absorption spectrophotometry are reported for 73 women of child bearing age resident in Los Angeles, California. The two quantities are related by the line y=0.00030+0.00241x (r=0.83), where y is serum lead concentration and x is blood lead concentration, both being expressed in units of microg/L. The linearity of the relationship appears to hold to a blood lead concentration of at least 60 microg Pb/L. The slope of the line indicates that lead in serum is 0.24% of that in whole blood in contrast to recent reports of between 0.32 and 0.35% determined by inductively coupled plasma (ICP) mass spectrometry with bismuth used as an internal standard. The discrepancy stems from the ICP mass spectrometer-generated curves not passing through the origin.

Adolescent↗
PubMed1996

Computer-assisted search for sites of nuclear matrix attachment.

This communication describes a useful approach for assessing the significance of the occurrence of multiple motifs within defined segments of the genome. Regions of potential biological importance are identified using various sequence motifs, and then the results are displayed as their cumulative statistically weighted distribution. We illustrate the utility of this strategy to the search for known nuclear matrix-associated regions by its application to the human beta-globin and other loci.

Algorithms↗
PubMed1994

Amino/aromatic interactions in proteins: is the evidence stacked against hydrogen bonding?

We investigate the suggestion that aromatic rings can act as hydrogen-bond acceptors in proteins, by an analysis of 55 non-homologous high-resolution protein chain structures. Approximately 10% of interactions between sp2 hybridized nitrogen atoms, from either side-chains or main-chains, and phenylalanine or tyrosine rings have the nitrogen atom positioned above the ring. In these instances, however, the sp2 nitrogen atoms tend to form stacked interactions with the aromatic rings, these geometries outnumbering amino/aromatic hydrogen bonds by around 2.5:1. The statistically expected distribution, in contrast, would have only a few stacked structures and many more with larger interplanar angles, corresponding to amino/aromatic hydrogen bonds. Thus, although we do find some of these unconventional hydrogen bonds, they are clearly disfavoured relative to stacked geometries. In stacked geometries, the nitrogen-bearing groups are observed to fulfil their hydrogen-bonding potential by forming conventional, energetically stronger, hydrogen bonds with other groups in protein or solvent. This may explain the favourability of stacking. Thus, although ab initio calculations of the gas phase interaction energies for three model systems generally favour the amino/aromatic hydrogen-bonded over the stacked geometries, the differences are small enough to be outweighed easily by the additional conventional hydrogen bonding in stacked structures.

Amino Acid Sequence↗
PubMed1998

Supersites within superfolds. Binding site similarity in the absence of homology.

A method is presented to assess the significance of binding site similarities within superimposed protein three-dimensional (3D) structures and applied to all similar structures in the Protein Data Bank. For similarities between 3D structures lacking significant sequence similarity, the important distinction was made between remote homology (an ancient common ancestor) and analogy (likely convergence to a folding motif) according to the structural classification of proteins (SCOP) database. Supersites were defined as structural locations on groups of analogous proteins (i.e. superfolds) showing a statistically significant tendency to bind substrates despite little evidence of a common ancestor for the proteins considered. We identify three potentially new superfolds containing supersites: ferredoxin-like folds, four-helical bundles and double-stranded beta helices. In addition, the method quantifies binding site similarities within homologous proteins and previously identified supersites such as that found in the beta/alpha (TIM) barrels. For the nine superfolds, the accuracy of predictions of binding site locations is assessed. Implications for protein evolution, and the prediction of protein function either through fold recognition or tertiary structure comparison, are discussed.

Animals↗
PubMed1999

Periodicity in alpha-helix lengths and C-capping preferences.

We surveyed 299 high resolution, non-homologous protein crystal structures for alpha-helix lengths and capping preferences. We find that helices show a preference to have close to an integral number of turns. Helices can be usefully subdivided into either "favoured length" with 6, 7, 10, 11, 13, 14, 17, 18, 21, 22, 24, 25, 28, 29 or 31 residues, or "disfavoured length" with 8, 9, 12, 15, 16, 19, 20, 23, 26, 27 or 30 residues. Favoured length helices have their N and C-caps on the same side of the helix so they can lie on the protein surface. There is no significant difference in amino acid preferences at the N terminus between favoured and disfavoured length helices. At the C terminus, favoured length helices prefer non-polar side-chains at C4 and polar amino acid residues at C2, while disfavoured length helices prefer non-polar amino acid residues at C2. There are strong periodic trends in the likelihood of terminating a helix with a Schellman or alphaL C-capping motif. These can be rationalised by the preference for a non-polar side-chain at C3 with these motifs, favouring placing C3 on the buried side of the helix. We suggest that algorithms aiming to predict helices or C-capping in proteins should include a weight for the helix length.

Algorithms↗
PubMed2000

The anatomy of protein beta-sheet topology.

Here, we present a systematic analysis of the open-faced beta-sheet topologies in a set of non-redundant protein domain structures; in particular, we focus on the topological diversity of four-stranded beta-sheet motifs. Of the 96 topologies that are possible for a four-stranded beta-sheet, 42 were identified in known protein structures. Of these, four account for 50% of the structures that we have studied. Two sets of the topologies that were not observed may represent the section of the topological space that is not readily accessible to proteins on either thermodynamic or kinetic grounds. The first set contains topologies with alternating parallel and antiparallel beta-ladders. Their rare occurrence reflects the expectation that it is energetically unfavorable to match different hydrogen bonding patterns. The polypeptide chains in the second set of topologies go through convoluted paths and are expected to experience great kinetic frustrations during the folding processes. A knowledge of the potential causes for the topological preference of small beta-sheets also helps us to understand the topological properties of larger beta-sheet structures which frequently contain four-stranded motifs. The notion that protein topologies can only be taken from a confined and discrete space has important implications for structural genomics.

Amino Acid Motifs↗
PubMed2000

Estimating the number of protein folds and families from complete genome data.

Using the data on proteins encoded in complete genomes, combined with a rigorous theory of the sampling process, we estimate the total number of protein folds and families, as well as the number of folds and families in each genome. The total number of folds in globular, water- soluble proteins is estimated at about 1000, with structural information currently available for about one-third of the number. The sequenced genomes of unicellular organisms encode from approximately 25%, for the minimal genomes of the Mycoplasmas, to 70-80% for larger genomes, such as Escherichia coli and yeast, of the total number of folds. The number of protein families with significant sequence conservation was estimated to be between 4000 and 7000, with structures available for about 20% of these.

Conserved Sequence↗
PubMed2002

Structural clusters of evolutionary trace residues are statistically significant and common in proteins.

Given the massive increase in the number of new sequences and structures, a critical problem is how to integrate these raw data into meaningful biological information. One approach, the Evolutionary Trace, or ET, uses phylogenetic information to rank the residues in a protein sequence by evolutionary importance and then maps those ranked at the top onto a representative structure. If these residues form structural clusters, they can identify functional surfaces such as those involved in molecular recognition. Now that a number of examples have shown that ET can identify binding sites and focus mutational studies on their relevant functional determinants, we ask whether the method can be improved so as to be applicable on a large scale. To address this question, we introduce a new treatment of gaps resulting from insertions and deletions, which streamlines the selection of sequences used as input. We also introduce objective statistics to assess the significance of the total number of clusters and of the size of the largest one. As a result of the novel treatment of gaps, ET performance improves measurably. We find evolutionarily privileged clusters that are significant at the 5% level in 45 out of 46 (98%) proteins drawn from a variety of structural classes and biological functions. In 37 of the 38 proteins for which a protein-ligand complex is available, the dominant cluster contacts the ligand. We conclude that spatial clustering of evolutionarily important residues is a general phenomenon, consistent with the cooperative nature of residues that determine structure and function. In practice, these results suggest that ET can be applied on a large scale to identify functional sites in a significant fraction of the structures in the protein databank (PDB). This approach to combining raw sequences and structure to obtain detailed insights into the molecular basis of function should prove valuable in the context of the Structural Genomics Initiative.

Binding Sites↗
PubMed1998

The immunologic role of IFN-gamma in ACI to Lewis kidney transplantation.

BACKGROUND: One of the proposed mechanisms of tolerance induction is the Th-1/Th-2 paradigm. The Th-1 cell is proinflammatory, secreting IFN-gamma and IL-2. Conversely, the Th-2 cell is anti-inflammatory, secreting IL-4 and IL-10. In our earlier studies a shift toward Th-2 dominance was required for tolerance induction in this model. MATERIALS AND METHODS: ACI and Lewis rats were used as donors and recipients, respectively. Twelve hours prior to engraftment, rapamycin 1.5 mg/kg po and cyclosporin 10 mg/kg sc were given, followed by 5 mg/kg sc postop (days 1-7). Lewis rats were used as isografts. Functional allograft tolerance was induced consistently in 100% of the recipients with 50% of the allografts exhibiting normal histology beyond 120 days. Qualitative RT-PCR was performed on the grafts to determine IFN-gamma expression with beta-actin housekeeping gene as control. RESULTS: IFN-gamma was expressed in all untreated allografts (5/5) and all treated, yet rejecting, allografts (4/4). None of the isografts (0/5) or histologically tolerant allografts (0/4) expressed IFN-gamma. This distribution was statistically significant (P < 0.001, Fischer's exact test). CONCLUSION: Our findings support a shift from Th-2 to Th-1 predominance as the corollary mechanism responsible for preventing histologic tolerance.

Animals↗
PubMedDate not supplied

Community-based surveillance of cardiovascular risk factors in Geneva: methods, resulting distributions, and comparisons with other populations.

OBJECTIVES: This paper presents the results of an ongoing community-based surveillance program of cardiovascular risk factors in Geneva, Switzerland, using percentiles with their associated 95% confidence intervals and compares the Genevan results with published data from international surveys reporting percentiles. METHODS: A random survey of adults ages 35 to 74 years was conducted from 1993 to 1994. Confidence intervals for percentiles based on parametric and non-parametric methods are given. RESULTS: The distribution of total cholesterol was shifted upward with increasing age. The median reached a maximum at 55-64 years among men (5.7 mmol/L) and at 65-74 years among women (5.9 mmol/L), and remained relatively stable thereafter. In both genders, systolic and, less so, diastolic blood pressure increased progressively with advancing age. The median daily energy intake among men declined from 2,390 kcal at age 35-44 years to 2,169 kcal at age 65-74 years, while among women it remained stable at about 1,900 kcal. In both males and females, the relative intake of saturated fat was stable throughout life (14 to 13%). The median body mass index (BMI) was about 25 kg/m2 across all age groups among men, but increased with age among women, with a peak of 23.6 kg/m2 occurring at ages 65-74 years. Compared with U.S. and western European surveys, Genevan men and women had lower total plasma cholesterol and Genevan women tended to have lower BMIs. CONCLUSIONS: Percentiles with their associated precision appear particularly well suited for international comparison of surveillance data. They could be used in the future to monitor shifts in distributions resulting from mass prevention strategies.

Adult↗