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Computerized scheme for determination of the likelihood measure of malignancy for pulmonary nodules on low-dose CT images.

An automated computerized scheme has been developed for determination of the likelihood measure of malignancy of pulmonary nodules on low-dose helical CT (LDCT) images. Our database consisted of 76 primary lung cancers (147 slices) and 413 benign nodules (576 slices). With this automated computerized scheme, the location of a nodule was first indicated by a radiologist. The outline of the nodule was segmented automatically by use of a dynamic programming technique. Various objective features on the nodules were determined by use of outline analysis and image analysis, and the likelihood measure of malignancy was determined by use of linear discriminant analysis (LDA). The effect of many different combinations of features and the performance of LDA in distinguishing benign nodules from malignant ones were evaluated by means of receiver operating characteristic (ROC) analysis. The Az value (area under the ROC curve) obtained by the computerized scheme in distinguishing benign nodules from malignant ones was 0.828 when a single slice was employed for each of the nodules. However, the Az value was improved to 0.846 when multiple slices were used for determination of the likelihood measure of malignancy. The Az values obtained by the computerized scheme on LDCT images were significantly greater than the Az value of 0.70, which was obtained from our previous observer studies by radiologists in distinguishing benign nodules from malignant ones on LDCT images. The automated computerized scheme for determination of the likelihood measure of malignancy would be useful in assisting radiologists to distinguish between benign and malignant pulmonary nodules on LDCT images.

Algorithms↗

Time normalization of voice signals using functional data analysis.

The harmonics-to-noise ratio (HNR) has been used to quantify the waveform irregularity of voice signals [Yumoto et al., J. Acoust. Soc. Am. 71, 1544-1550 (1982)]. This measure assumes that the signal consists of two components: a harmonic component, which is the common pattern that repeats from cycle-to-cycle, and an additive noise component, which produces the cycle-to-cycle irregularity. It has been shown [J. Qi, J. Acoust. Soc. Am. 92, 2569-2576 (1992)] that a valid computation of the HNR requires a nonlinear time normalization of the cycle wavelets to remove phase differences between them. This paper shows the application of functional data analysis to perform an optimal nonlinear normalization and compute the HNR of voice signals. Results obtained for the same signals using zero-padding, linear normalization, and dynamic programming algorithms are presented for comparison. Functional data analysis offers certain advantages over other approaches: it preserves meaningful features of signal shape, produces differentiable results, and allows flexibility in selecting the optimization criteria for the wavelet alignment. An extension of the technique for the time normalization of simultaneous voice signals (such as acoustic, EGG, and airflow signals) is also shown. The general purpose of this article is to illustrate the potential of functional data analysis as a powerful analytical tool for studying aspects of the voice production process.

Data Interpretation, Statistical↗

Automated detection of the tongue surface in sequences of ultrasound images.

An image processing system has been developed for a Macintosh II personal computer. It is designed to process sequences of sagittal tongue sections that are digitized in real time and stored in standard tagged image file format (TIFF). The successive processing steps are: (a) a low-pass filter for noise reduction, (b) a resampling of the sector of interest in polar coordinates, (c) a matched filter (vertical differentiator) for the enhancement of the tissue/air interface in the surface region of the tongue, and (d) an extraction of border points by searching for an optimal radial path along the angular dimension. This latter task is achieved by dynamic programming, which has the following advantages. First, due to the use of a global criterion to guide the detection, it is very robust. Second, as a result of certain restrictions of the allowable transitions, the extracted contours are smooth. Finally, the method permits the specification of particular predefined contour points. This system was implemented in a program that can handle image sequences in a fully automatic mode. Results obtained using ultrasound data are presented.

Humans↗

A new computational method for detection of chimeric 16S rRNA artifacts generated by PCR amplification from mixed bacterial populations.

A new computational method (chimeric alignment) has been developed to detect chimeric 16S rRNA artifacts generated during PCR amplification from mixed bacterial populations. In contrast to other nearest-neighbor methods (e.g., CHECK_CHIMERA) that define sequence similarity by k-tuple matching, the chimeric alignment method uses the score from dynamic programming alignments. Further, the chimeric alignments are displayed to the user to assist in sequence classification. The distribution of improvement scores for 500 authentic, nonchimeric sequences and 300 artificial chimeras (constructed from authentic sequences) was used to study the sensitivity and accuracy of both chimeric alignment and CHECK_CHIMERA. At a constant rate of authentic sequence misclassification (5%), chimeric alignment incorrectly classified 13% of the artificial chimeras versus 14% for CHECK_CHIMERA. Interestingly, only 1% of nonchimeras and 10% of chimeras were misclassified by both programs, suggesting that optimum performance is obtained by using the two methods to assign sequences to three classes: high-probability nonchimeras, high-probability chimeras, and sequences that need further study by other means. This study suggests that k-tuple-based matching methods are more sensitive than alignment-based methods when there is significant parental sequence similarity, while the opposite becomes true as the sequences become more distantly related. The software and a World Wide Web-based server are available at http://www-hto.usc.edu/software/mglobal CHI.

Bacteria↗

The economics of culling dairy cows with clinical mastitis.

Culling dairy cows with clinical mastitis reduces the incidence of the disease in dairy herds, but the costs of such action, in terms of reduced milk production and increased replacement costs, are generally thought to outweigh the benefits. To test this hypothesis a stochastic dynamic programming model was developed to establish the economically optimum time of replacement for dairy cows subject to variable levels of clinical mastitis infection, using average United Kingdom production and price parameters. The optimal stage at which to replace a dairy cow was found to be sensitive to changes in mastitis incidence and in critical price parameters within the bounds of commercial experience. This result indicates that an objective culling policy based on clinical mastitis records in addition to milk production potential may be economically viable.

Animals↗

Financial incentive to control paratuberculosis (Johne's disease) on dairy farms in the United Kingdom.

This paper estimates the financial incentive to control paratuberculosis on dairy farms by establishing the level of expenditure that would minimise the total cost of the disease (output losses plus control expenditure). Given the late onset of the clinical signs and the lack of treatments, control was focused on minimising the financial impact of paratuberculosis by adjusting the dairy cow replacement policy. The optimum replacement policies for disease-free herds and infected herds were compared by using dynamic programming. At the standard settings, the disease justified adjusting the culling policy; under constant bioeconomic assumptions, it reduced the expected annuity from milk production under the optimal replacement policy by about 10 per cent (27 pounds sterling per cow annually), a considerably lower figure than for other major endemic diseases that affect dairy cows in the uk. The effect was even less at lower milk prices, suggesting that there is at present little incentive for dairy farmers to put more resources into controlling the disease. However, the incentive could be increased if more information were available about how best to manage the disease under specific farm circumstances. Any effect that paratuberculosis may have on the future demand for milk and hence on milk prices would also be an important consideration.

Animals↗

An MDL method for finding haplotype blocks and for estimating the strength of haplotype block boundaries.

We describe a new method for finding haplotype blocks based on the use of the minimum description length principle. We give a rigorous definition of the quality of a segmentation of a genomic region into blocks, and describe a dynamic programming algorithm for finding the optimal segmentation with respect to this measure. We also describe a method for finding the probability of a block boundary for each pair of adjacent markers: this gives a tool for evaluating the significance of each block boundary. We have applied the method to the published data of Daly et al. The results are in relatively good agreement with the published results, but also show clear differences in the predicted block boundaries and their strengths. We also give results on the block structure in population isolates.

Algorithms↗

Pairwise RNA structure comparison with stochastic context-free grammars.

Pairwise stochastic context-free grammars ("Pair SCFGs") are powerful tools for finding conserved RNA structures, but unconstrained alignment to Pair SCFGs is prohibitively expensive. We develop versions of the Pair SCFG dynamic programming algorithms that can be conditioned on precomputed structures, significantly reducing the time complexity of alignment. We have implemented these algorithms for general Pair SCFGs in software that is freely available under the GNU Public License.

Algorithms↗

Folding nuclei in 3D protein structures.

This paper presents and analyzes the results of several new approaches to the problem of finding the folding nucleus in a given 3D protein structure. Firstly, we show that the participation of residues in the hydrophobic core and the secondary structure of native protein has a rather modest correlation with the experimentally found phi values characterizing the participation of residues in the folding nuclei. Then we tried to find the nuclei as the free energy saddle points on the network of the folding/unfolding pathways using the branch-and-bound technique and dynamic programming. We also attempted to estimate the phi values from solving of kinetic equations for the network of protein folding/unfolding pathways. These approaches give a better correlation with experiment, and the estimated folding time is consistent with the experimentally observed rapid folding of small proteins.

Computer Simulation↗

A fast and sensitive algorithm for aligning ESTs to the human genome.

There is a pressing need to align the growing set of expressed sequence tags (ESTs) with the newly sequenced human genome. However, the problem is complicated by the exon/intron structure of eukaryotic genes misread nucleotides in ESTs, and the millions of repetitive sequences in genomic sequences. To solve this problem, algorithms that use dynamic programming have been proposed. In reality, however, these algorithms require an enormous amount of processing time. In an effort to improve the computational efficiency of these classical DP algorithms, we developed software that fully utilizes lookup-tables to detect the start- and endpoints of an EST within a given DNA sequence efficiently, and subsequently promptly identify exons and introns. In addition, the locations of all splice sites must be calculated correctly with high sensitivity and accuracy, while retaining high computational efficiency. This goal is hard to accomplish in practice, due to misread nucleotides in ESTs and repetitive sequences in the genome. Nevertheless, we present two heuristics that effectively settle this issue. Experimental results confirm that our technique improves the overall computation time by orders of magnitude compared with common tools, such as SIM4 and BLAT, and simultaneously attains high sensitivity and accuracy against a clean dataset of documented genes.

Algorithms↗

Computing highly specific and noise-tolerant oligomers efficiently.

The sequencing of the genomes of a variety of species and the growing databases containing expressed sequence tags (ESTs) and complementary DNAs (cDNAs) facilitate the design of highly specific oligomers for use as genomic markers, PCR primers, or DNA oligo microarrays. The first step in evaluating the specificity of short oligomers of about 20 units in length is to determine the frequencies at which the oligomers occur. However, for oligomers longer than about fifty units this is not efficient, as they usually have a frequency of only 1. A more suitable procedure is to consider the mismatch tolerance of an oligomer, that is, the minimum number of mismatches that allows a given oligomer to match a substring other than the target sequence anywhere in the genome or the EST database. However, calculating the exact value of mismatch tolerance is computationally costly and impractical. Therefore, we studied the problem of checking whether an oligomer meets the constraint that its mismatch tolerance is no less than a given threshold. Here, we present an efficient dynamic programming algorithm solution that utilizes suffix and height arrays. We demonstrated the effectiveness of this algorithm by efficiently computing a dense list of numerous oligo-markers applicable to the human genome. Experimental results show that the algorithm runs faster than well-known Abrahamson's algorithm by orders of magnitude and is able to enumerate 65% approximately 76% of qualified oligomers.

Algorithms↗

Identifying uniformly mutated segments within repeats.

Given a long string of characters from a constant size alphabet we present an algorithm to determine whether its characters have been generated by a single i.i.d. random source. More specifically, consider all possible n-coin models for generating a binary string S, where each bit of S is generated via an independent toss of one of the n coins in the model. The choice of which coin to toss is decided by a random walk on the set of coins where the probability of a coin change is much lower than the probability of using the same coin repeatedly. We present a procedure to evaluate the likelihood of a n-coin model for given S, subject a uniform prior distribution over the parameters of the model (that represent mutation rates and probabilities of copying events). In the absence of detailed prior knowledge of these parameters, the algorithm can be used to determine whether the a posteriori probability for n=1 is higher than for any other n>1. Our algorithm runs in time O(l4logl), where l is the length of S, through a dynamic programming approach which exploits the assumed convexity of the a posteriori probability for n. Our test can be used in the analysis of long alignments between pairs of genomic sequences in a number of ways. For example, functional regions in genome sequences exhibit much lower mutation rates than non-functional regions. Because our test provides means for determining variations in the mutation rate, it may be used to distinguish functional regions from non-functional ones. Another application is in determining whether two highly similar, thus evolutionarily related, genome segments are the result of a single copy event or of a complex series of copy events. This is particularly an issue in evolutionary studies of genome regions rich with repeat segments (especially tandemly repeated segments).

Algorithms↗

Pairwise protein structure alignment based on an orientation-independent backbone representation.

Determining structural similarities between proteins is an important problem since it can help identify functional and evolutionary relationships. In this paper, an algorithm is proposed to align two protein structures. Given the protein backbones, the algorithm finds a rigid motion of one backbone onto the other such that large substructures are matched. The algorithm uses a representation of the backbones that is independent of their relative orientations in space and applies dynamic programming to this representation to compute an initial alignment, which is then refined iteratively. Experiments indicate that the algorithm is competitive with two well-known algorithms, namely DALI and LOCK.

Algorithms↗

Rnall: an efficient algorithm for predicting RNA local secondary structural landscape in genomes.

BACKGROUND: The information of RNA local secondary structures (LSSs) can help retrieve biologically important motifs and study functions of RNA molecules. Most of the current RNA secondary structure prediction tools are not suitable for RNA LSS prediction on the genome scale due to high computational complexity. METHODS: We developed a new computer package Rnall based on a dynamic programming technique, which scans an RNA sequence with a sliding window and extracts all RNA LSSs with sizes no larger than the window size using the nearest neighbor thermodynamic parameters. The worst case running time of Rnall is O(W(3)L), where W is the window size and L is the query sequence length. In practice we observed a running time of O(W(2)L). We further introduced the concept of energy landscape for illustrating RNA LSS, which may facilitate RNA motif mining on the genomic scale. RESULTS: Rnall shows better prediction accuracy than two other prediction tools Lfold and Quickfold. Rnall is also applied to scan for RNA LSSs in three genomes, and the prediction maps well with known RNA motifs. CONCLUSIONS: Rnall is designed for RNA LSS prediction and together with the energy landscape, it has unique features that could be used for RNA structural motif mining. Rnall is freely available for download at http://digbio.missouri.edu/~wanx/Rnall or http://www.sysbio.muohio.edu/Rnall.

Algorithms↗

The thermodynamics of DNA structural motifs.

DNA secondary structure plays an important role in biology, genotyping diagnostics, a variety of molecular biology techniques, in vitro-selected DNA catalysts, nanotechnology, and DNA-based computing. Accurate prediction of DNA secondary structure and hybridization using dynamic programming algorithms requires a database of thermodynamic parameters for several motifs including Watson-Crick base pairs, internal mismatches, terminal mismatches, terminal dangling ends, hairpins, bulges, internal loops, and multibranched loops. To make the database useful for predictions under a variety of salt conditions, empirical equations for monovalent and magnesium dependence of thermodynamics have been developed. Bimolecular hybridization is often inhibited by competing unimolecular folding of a target or probe DNA. Powerful numerical methods have been developed to solve multistate-coupled equilibria in bimolecular and higher-order complexes. This review presents the current parameter set available for making accurate DNA structure predictions and also points to future directions for improvement.

Algorithms↗

Selecting loop breakers in general pedigrees.

The presence of loops in pedigrees poses severe computational problems in likelihood calculation that can be solved by creating an equivalent unlooped pedigree. We introduce a heuristic polynomial-time dynamic-programming algorithm, called SFH, that addresses the problem of selecting a minimal-cost set of loop breakers. We report computational experiments on simulated pedigrees with up to 1000 individuals and 361 loops, and multiple marriages. We compare the loop-breaker set selected by our method with that obtained using the software package FASTLINK 4.1P. Our approach outperforms FASTLINK 4.1P on the computational-time point of view, on the point of view of quality of the loop-breaker set obtained, and on the point of view of the size of the problem that can be addressed.

Algorithms↗

Fluid dynamics of the cerebral aqueduct.

Despite a multitude of theories describing the mechanics of the intracranial spaces in diseases such as hydrocephalus, little is known about the mechanics of normal CSF flow. A pressure difference is required to drive CSF flow. Knowing that the pressure difference driving fluid through the aqueduct is beyond the resolution of clinically used pressure transducers, a computational fluid dynamics program was used to analyze flow through an aqueduct shape. Flow through this duct was compared with that through a cylinder and through a double hourglass. Both steady and oscillating flows were tested, revealing that only 1.1 Pa of pressure is required to move CSF through the aqueduct. This suggests that normally less than 5% of the total resistance to CSF flow within the CSF pathways occurs in the aqueduct.

Cerebral Aqueduct↗

Ultrasound measurement of the fibrous cap in symptomatic and asymptomatic atheromatous carotid plaques.

BACKGROUND: Fibrous cap thickness (FCT) is an important determinant of atheroma stability. We evaluated the feasibility and potential clinical implications of measuring the FCT of internal carotid artery plaques with a new ultrasound system based on boundary detection by dynamic programming. METHODS AND RESULTS: We assessed agreement between ultrasound-obtained FCT values and those measured histologically in 20 patients (symptomatic [S]=9, asymptomatic [AS]=11) who underwent carotid endarterectomy for stenosing (>70%) carotid atheromas. We subsequently measured in vivo the FCT of 58 stenosing internal carotid artery plaques (S=22, AS=36) in 54 patients. The accuracy in discriminating symptomatic from asymptomatic plaques was assessed by receiver operating characteristic curves for the minimal, mean, and maximal FCT. Decision FCT thresholds that provided the best correct classification rates were identified. Agreement between ultrasound and histology was excellent, and interobserver variability was small. Ultrasound showed that symptomatic atheromas had thinner fibrous caps (S versus AS, median [95% CI]: minimal FCT=0.42 [0.34 to 0.48] versus 0.50 [0.44 to 0.53] mm, P=0.024; mean FCT=0.58 [0.52 to 0.63] versus 0.79 [0.69 to 0.85] mm, P<0.0001; maximal FCT=0.73 [0.66 to 0.92] versus 1.04 [0.94 to 1.20] mm, P<0.0001). Mean FCT measurement demonstrated the best discriminatory accuracy (area under the curve [95% CI]: minimal 0.74 [0.61 to 0.87]; mean 0.88 [0.79 to 0.97]; maximal 0.82 [0.71 to 0.93]). The decision threshold of 0.65 mm (mean FTC) demonstrated the best correct classification rate (82.8%; positive predictive value 75%, negative predictive value 88.2%). CONCLUSIONS: FCT measurement of carotid atheroma with ultrasound is feasible. Discrimination of symptomatic from asymptomatic plaques with mean FCT values is good. Prospective studies should determine whether this ultrasound marker is reliable.

Aged↗