Biomedical subjects

A Lapedes

Publications and source records attributed to A Lapedes.

5 recordsLinked to original sources

PubMed2001

The geometry of shape space: application to influenza.

Shape space was proposed over 20 years ago as a conceptual formalism in which to represent antibody/antigen binding. It has since played a key role in computational immunology. Antigens and antibodies are considered to be points in an abstract "shape space", where coordinates of points in this space represent generalized physico-chemical properties associated with various (unspecified) physical properties related to binding, such as geometric shape, hydrophobicity, charge, etc. Distances in shape space between points representing antibodies and (the shape complement) of antigens are assumed to be related to their affinity, with small distances corresponding to high affinity. In this paper, we provide algorithms, related to metric and ordinal multidimensional scaling algorithms first developed in the mathematical psychology literature, which construct explicit, quantitative coordinates for points in shape space given experimental data such as hemagglutination inhibition assays, or other general affinity assays. Previously, such coordinates had been conceptual constructs and totally implicit. The dimension of shape space deduced from hemagglutination inhibition assays for influenza is low, approximately five dimensional. The deduction of the explicit geometry of shape space given experimental affinity data provides new ways to quantify the similarity of antibodies to antibodies, antigens to antigens, and the affinity of antigens to antibodies. This has potential utility in, e.g. strain selection decisions for annual influenza vaccines, among other applications. The analysis techniques presented here are not restricted to the analysis of antibody-antigen interactions and are generally applicable to affinity data resulting from binding assays.

Algorithms↗

PubMed2000

Timing the ancestor of the HIV-1 pandemic strains.

HIV-1 sequences were analyzed to estimate the timing of the ancestral sequence of the main group of HIV-1, the strains responsible for the AIDS pandemic. Using parallel supercomputers and assuming a constant rate of evolution, we applied maximum-likelihood phylogenetic methods to unprecedented amounts of data for this calculation. We validated our approach by correctly estimating the timing of two historically documented points. Using a comprehensive full-length envelope sequence alignment, we estimated the date of the last common ancestor of the main group of HIV-1 to be 1931 (1915-41). Analysis of a gag gene alignment, subregions of envelope including additional sequences, and a method that relaxed the assumption of a strict molecular clock also supported these results.

Acquired Immunodeficiency Syndrome↗

PubMed1995

Neural net representations of empirical protein potentials.

Recently, there has been considerable interest in deriving and applying knowledge-based, empirical potential functions for proteins. These empirical potentials have been derived from the statistics of interacting, spatially neighboring residues, as may be obtained from databases of known protein crystal structures. In this paper we employ neural networks to redefine empirical potential functions from the point of view of discrimination functions. This approach generalizes previous work, in which simple frequency counting statistics are used on a database of known protein structures. This generalization allows us to avoid restriction to strictly pairwise interactions. Instead of frequency counting to fix adjustable parameters, one now optimizes an objective function involving a neural network parameterized probability distribution. We show how our method reduces to previous work in special situations, but also allows extensions to include orders of interaction beyond pairwise interaction. Given the close packing of proteins, steric interactions etc., the inclusion of higher order interactions is critical for developing an accurate potential. A key feature in the approach we advocate is the development of a representation to describe the spatial location of interacting residues that exist in a sphere of small fixed radius around each residue. This is a "shape representation" problem that has a natural solution for the interaction neighborhoods of protein residues. We demonstrate in a series of numerical experiments that the neural network approach improves discrimination over that obtained by previous methodologies limited to pair-wise interactions.

Amino Acid Sequence↗

PubMed1992

Determination of eukaryotic protein coding regions using neural networks and information theory.

Our previous work applied neural network techniques to the problem of discriminating open reading frame (ORF) sequences taken from introns versus exons. The method counted the codon frequencies in an ORF of a specified length, and then used this codon frequency representation of DNA fragments to train a neural net (essentially a Perceptron with a sigmoidal, or "soft step function", output) to perform this discrimination. After training, the network was then applied to a disjoint "predict" set of data to assess accuracy. The resulting accuracy in our previous work was 98.4%, exceeding accuracies reported in the literature at that time for other algorithms. Here, we report even higher accuracies stemming from calculations of mutual information (a correlation measure) of spatially separated codons in exons, and in introns. Significant mutual information exists in exons, but not in introns, between adjacent codons. This suggests that dicodon frequencies of adjacent codons are important for intron/exon discrimination. We report that accuracies obtained using a neural net trained on the frequency of dicodons is significantly higher at smaller fragment lengths than even our original results using codon frequencies, which were already higher than simple statistical methods that also used codon frequencies. We also report accuracies obtained from including codon and dicodon statistics in all six reading frames, i.e. the three frames on the original and complement strand. Inclusion of six-frame statistics increases the accuracy still further. We also compare these neural net results to a Bayesian statistical prediction method that assumes independent codon frequencies in each position. The performance of the Bayesian scheme is poorer than any of the neural based schemes, however many methods reported in the literature either explicitly, or implicitly, use this method. Specifically, Bayesian prediction schemes based on codon frequencies achieve 90.9% accuracy on 90 codon ORFs, while our best neural net scheme reaches 99.4% accuracy on 60 codon ORFs. "Accuracy" is defined as the average of the exon and intron sensitivities. Achievement of sufficiently high accuracies on short fragment lengths can be useful in providing a computational means of finding coding regions in unannotated DNA sequences such as those arising from the mega-base sequencing efforts of the Human Genome Project. We caution that the high accuracies reported here do not represent a complete solution to the problem of identifying exons in "raw" base sequences. The accuracies are considerably lower from exons of small length, although still higher than accuracies reported in the literature for other methods. Short exon lengths are not uncommon.(ABSTRACT TRUNCATED AT 400 WORDS)

Base Sequence↗

PubMed1992

Predicting protein secondary structure using neural net and statistical methods.

A comparison of neural network methods and Bayesian statistical methods is presented for prediction of the secondary structure of proteins given their primary sequence. The Bayesian method makes the unphysical assumption that the probability of an amino acid occurring in each position in the protein is independent of the amino acids occurring elsewhere. However, we find the predictive accuracy of the Bayesian method to be only minimally less than the accuracy of the most sophisticated methods used to date. We present the relationship of neural network methods to Bayesian statistical methods and show that, in principle, neural methods offer considerable power, although apparently they are not particularly useful for this problem. In the process, we derive a neural formalism in which the output neurons directly represent the conditional probabilities of structure class. The probabilistic formalism allows introduction of a new objective function, the mutual information, which translates the notion of correlation as a measure of predictive accuracy into a useful training measure. Although a similar accuracy to other approaches (utilizing a mean-square error) is achieved using this new measure, the accuracy on the training set is significantly and tantalizingly higher, even though the number of adjustable parameters remains the same. The mutual information measure predicts a greater fraction of helix and sheet structures correctly than the mean-square error measure, at the expense of coil accuracy, precisely as it was designed to do. By combining the two objective functions, we obtain a marginally improved accuracy of 64.4%, with Matthews coefficients C alpha, C beta and Ccoil of 0.40, 0.32 and 0.42, respectively. However, since all methods to date perform only slightly better than the Bayes algorithm, which entails the drastic assumption of independence of amino acids, one is forced to conclude that little progress has been made on this problem, despite the application of a variety of sophisticated algorithms such as neural networks, and that further advances will require a better understanding of the relevant biophysics.

Bayes Theorem↗