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Controlling the false positive rate in fuzzy clustering using randomization: application to fMRI activation detection.

Despite its potential advantages for fMRI analysis, fuzzy C-means (FCM) clustering suffers from limitations such as the need for a priori knowledge of the number of clusters, and unknown statistical significance and instability of the results. We propose a randomization-based method to control the false-positive rate and estimate statistical significance of the FCM results. Using this novel approach, we develop an fMRI activation detection method. The ability of the method in controlling the false-positive rate is shown by analysis of false positives in activation maps of resting-state fMRI data. Controlling the false-positive rate in FCM allows comparison of different fuzzy clustering methods, using different feature spaces, to other fMRI detection methods. In this article, using simulation and real fMRI data, we compare a novel feature space that takes the variability of the hemodynamic response function into account (HRF-based feature space) to the conventional cross-correlation analysis and FCM using the cross-correlation feature space. In both cases, the HRF-based feature space provides a greater sensitivity compared to the cross-correlation feature space and conventional cross-correlation analysis. Application of the proposed method to finger-tapping fMRI data, using HRF-based feature space, detected activation in sub-cortical regions, whereas both of the FCM with cross-correlation feature space and the conventional cross-correlation method failed to detect them.

Algorithms↗

Object-of-interest image segmentation based on human attention and semantic region clustering.

We propose a novel object-of-interest (OOI) segmentation algorithm for various images that is based on human attention and semantic region clustering. As object-based image segmentation is beyond current computer vision techniques, the proposed method segments an image into regions, which are then merged as a semantic object. At the same time, an attention window (AW) is created based on the saliency map and saliency points from an image. Within the AW, a support vector machine is used to select the salient regions, which are then clustered into the OOI using the proposed region merging. Unlike other algorithms, the proposed method allows multiple OOIs to be segmented according to the saliency map.

Algorithms↗

Evaluation of QRS morphological classifiers in the presence of noise.

This paper analyzes the performance of four similarity measures (distances: d1, d2, and dinfinity, as well as correlation coefficient), when they are employed for morphological classification of QRS complexes by means of linear cluster formation. An important characteristic that any morphological classification method for QRS complexes should possess is the ability to perform waveform recognition despite the wide variety in which these could appear, as well as the diverse types of noise that could contaminate the signal. Evaluation of these classifiers constitutes an important problem for their selection. Evaluation was performed using electrocardiographic signals selected from the MIT-BIH database. These signals were contaminated with several noise types that are found in the environment where electrocardiograms are usually registered and processed, and the different noise waveforms were combined in an appropriate way to simulate practical situations, including some with severe noise contamination. Results are expressed in terms of probabilities of correct classification for different signal to noise ratios, allowing a comparison between the different distance measures in terms of their effectiveness.

Algorithms↗

Fast formation of statistically reliable FDG parametric images based on clustering and principal components.

Formation of parametric images requires voxel-by-voxel estimation of rate constants, a process sensitive to noise and computationally demanding. A model-based clustering method for a two-parameter model (CAKS) was extended to the FDG three-parameter model. The concept was to average voxels with similar kinetic signatures to reduce noise. Voxel kinetics were categorized by the first two principal components of the tissue time-activity curves for all voxels. k2 and k3 were estimated cluster-by-cluster, and K1 was estimated voxel-by-voxel within clusters. When CAKS was applied to simulated images with noise levels similar to brain FDG scans, estimation bias was well suppressed, and estimation errors were substantially smaller--1.3 times for Ki and 1.5 times for k3-than those of conventional voxel-based estimation. The statistical reliability of voxel-level estimation by CAKS was comparable with ROI analysis including 100 voxels. CAKS was applied to clinical cases with Alzheimer's disease (ALZ) and cortico basal degeneration (CBD). In ALZ, the affected regions had low Ki (K1k3/(k2 +k3)) and k3. In CBD, Ki was low, but k3 was preserved. These results were consistent with ROI-based kinetic analysis. Because CAKS decreased the number of invoked estimations, the calculation time was reduced substantially. In conclusion, CAKS has been extended to allow parametric imaging of a three-compartment model. The method is computationally efficient. with low bias and excellent noise properties.

Algorithms↗

Clustering biological annotations and gene expression data to identify putatively co-regulated biological processes.

MOTIVATION: Functional profiling is a key step of microarray gene expression data analysis. Identifying co-regulated biological processes could help for better understanding of underlying biological interactions within the studied biological frame. RESULTS: We present herein an original approach designed to search for putatively co-regulated biological processes sharing a significant number of co-expressed genes. An R language implementation named "FunCluster" was built and tested on two gene expression data sets. A discriminatory functional analysis of the first data set, related to experiments performed on separated adipocytes and stroma vascular fraction cells of human white adipose tissue, highlighted the prevalent role of nonadipose cells in the synthesis of inflammatory and immunity molecules in human adiposity. On the second data set, resulting from a model investigating insulin coordinated regulation of gene expression in human skeletal muscle, FunCluster analysis spotlighted novel functional classes of putatively co-regulated biological processes related to protein metabolism and the regulation of muscular contraction. AVAILABILITY: Supplementary information about the FunCluster tool is available on-line at http://corneliu.henegar.info/FunCluster.htm.

Algorithms↗

A preliminary examination of genetic variation in a peripheral population of Blanding's turtle, Emydoidea blandingii.

Random amplified polymorphic DNA (RAPD) was used to compare the Nova Scotia population of Blanding's turtle (Emydoidea blandingii) with several populations from the species' main range. The Nova Scotia population is believed to have been isolated from the main range for 4000-8000 years. Cluster analysis using a neighbour-joining algorithm produced a dendrogram showing the Nova Scotia population clustering separately from those populations in the main range. Analysis of molecular variance shows 34.28% of total variance to be accounted for between the Nova Scotia population and populations in the main range. While this study is preliminary, the results suggest that the Nova Scotia population of Blanding's turtle may be important to the maintenance of genetic diversity in the species.

Analysis of Variance↗

ECgene: genome-based EST clustering and gene modeling for alternative splicing.

With the availability of the human genome map and fast algorithms for sequence alignment, genome-based EST clustering became a viable method for gene modeling. We developed a novel gene-modeling method, ECgene (Gene modeling by EST Clustering), which combines genome-based EST clustering and the transcript assembly procedure in a coherent and consistent fashion. Specifically, ECgene takes alternative splicing events into consideration. The position of splice sites (i.e., exon-intron boundaries) in the genome map is utilized as the critical information in the whole procedure. Sequences that share any splice sites are grouped together to define an EST cluster in a manner similar to that of the genome-based version of the UniGene algorithm. Transcript assembly is achieved using graph theory that represents the exon connectivity in each cluster as a directed acyclic graph (DAG). Distinct paths along exons correspond to possible gene models encompassing all alternative splicing events. EST sequences in each cluster are subclustered further according to the compatibility with gene structure of each splice variant, and they can be regarded as clone evidence for the corresponding isoform. The reliability of each isoform is assessed from the nature of cluster members and from the minimum number of clones required to reconstruct all exons in the transcript.

Algorithms↗

PAQ: Partition Analysis of Quasispecies.

MOTIVATION: The complexities of genetic data may not be accurately described by any single analytical tool. Phylogenetic analysis is often used to study the genetic relationship among different sequences. Evolutionary models and assumptions are invoked to reconstruct trees that describe the phylogenetic relationship among sequences. Genetic databases are rapidly accumulating large amounts of sequences. Newly acquired sequences, which have not yet been characterized, may require preliminary genetic exploration in order to build models describing the evolutionary relationship among sequences. There are clustering techniques that rely less on models of evolution, and thus may provide nice exploratory tools for identifying genetic similarities. Some of the more commonly used clustering methods perform better when data can be grouped into mutually exclusive groups. Genetic data from viral quasispecies, which consist of closely related variants that differ by small changes, however, may best be partitioned by overlapping groups. RESULTS: We have developed an intuitive exploratory program, Partition Analysis of Quasispecies (PAQ), which utilizes a non-hierarchical technique to partition sequences that are genetically similar. PAQ was used to analyze a data set of human immunodeficiency virus type 1 (HIV-1) envelope sequences isolated from different regions of the brain and another data set consisting of the equine infectious anemia virus (EIAV) regulatory gene rev. Analysis of the HIV-1 data set by PAQ was consistent with phylogenetic analysis of the same data, and the EIAV rev variants were partitioned into two overlapping groups. PAQ provides an additional tool which can be used to glean information from genetic data and can be used in conjunction with other tools to study genetic similarities and genetic evolution of viral quasispecies.

Algorithms↗

Using laboratory-based surveillance data for prevention: an algorithm for detecting Salmonella outbreaks.

By applying cumulative sums (CUSUM), a quality control method commonly used in manufacturing, we constructed a process for detecting unusual clusters among reported laboratory isolates of disease-causing organisms. We developed a computer algorithm based on minimal adjustments to the CUSUM method, which cumulates sums of the differences between frequencies of isolates and their expected means; we used the algorithm to identify outbreaks of Salmonella Enteritidis isolates reported in 1993. By comparing these detected outbreaks with known reported outbreaks, we estimated the sensitivity, specificity, and false-positive rate of the method. Sensitivity by state in which the outbreak was reported was 0%(0/1) to 100%. Specificity was 64% to 100%, and the false-positive rate was 0 to 1.

Algorithms↗

Molecular phenotyping of human endometrium distinguishes menstrual cycle phases and underlying biological processes in normo-ovulatory women.

Histological evaluation of endometrium has been the gold standard for clinical diagnosis and management of women with endometrial disorders. However, several recent studies have questioned the accuracy and utility of such evaluation, mainly because of significant intra- and interobserver variations in histological interpretation. To examine the possibility that biochemical or molecular signatures of endometrium may prove to be more useful, we have investigated whole-genome molecular phenotyping (54,600 genes and expressed sequence tags) of this tissue sampled across the cycle in 28 normo-ovulatory women, using high-density oligonucleotide microarrays. Unsupervised principal component analysis of all samples revealed that samples self-cluster into four groups consistent with histological phenotypes of proliferative (PE), early-secretory (ESE), mid-secretory (MSE), and late-secretory (LSE) endometrium. Independent hierarchical clustering analysis revealed equivalent results, with two major dendrogram branches corresponding to PE/ESE and MSE/LSE and sub-branching into the four respective phases with heterogeneity among samples within each sub-branch. K-means clustering of genes revealed four major patterns of gene expression (high in PE, high in ESE, high in MSE, and high in LSE), and gene ontology analysis of these clusters demonstrated cycle-phase-specific biological processes and molecular functions. Six samples with ambiguous histology were identically assignable to a cycle phase by both principal component analysis and hierarchical clustering. Additionally, pairwise comparisons of relative gene expression across the cycle revealed genes/families that clearly distinguish the transitions of PE-->ESE, ESE-->MSE, and MSE-->LSE, including receptomes and signaling pathways. Select genes were validated by quantitative RT-PCR. Overall, the results demonstrate that endometrial samples obtained by two different sampling techniques (biopsy and curetting hysterectomy specimens) from subjects who are as normal as possible in a human study and including those with unknown histology, can be classified by their molecular signatures and correspond to known phases of the menstrual cycle with identical results using two independent analytical methods. Also, the results enable global identification of biological processes and molecular mechanisms that occur dynamically in the endometrium in the changing steroid hormone milieu across the menstrual cycle in normo-ovulatory women. The results underscore the potential of gene expression profiling for developing molecular diagnostics of endometrial normalcy and abnormalities and identifying molecular targets for therapeutic purposes in endometrial disorders.

Adult↗

Cd-hit: a fast program for clustering and comparing large sets of protein or nucleotide sequences.

MOTIVATION: In 2001 and 2002, we published two papers (Bioinformatics, 17, 282-283, Bioinformatics, 18, 77-82) describing an ultrafast protein sequence clustering program called cd-hit. This program can efficiently cluster a huge protein database with millions of sequences. However, the applications of the underlying algorithm are not limited to only protein sequences clustering, here we present several new programs using the same algorithm including cd-hit-2d, cd-hit-est and cd-hit-est-2d. Cd-hit-2d compares two protein datasets and reports similar matches between them; cd-hit-est clusters a DNA/RNA sequence database and cd-hit-est-2d compares two nucleotide datasets. All these programs can handle huge datasets with millions of sequences and can be hundreds of times faster than methods based on the popular sequence comparison and database search tools, such as BLAST.

Algorithms↗

Reliable computer-assisted classification of the EEG: EEG variants in index cases and their first degree relatives.

A method which optimizes on global properties of sample recordings is proposed for the definition of and the discrimination between electroencephalogram (EEG) classes. The sample was drawn from students at the University of Heidelberg from 1974 to 1978 and consists of 15 healthy index cases clinically ascertained as belonging to the low voltage EEG group. In addition, the three clinically defined groups: diffuse beta (18 index cases), borderline alpha (12 index cases) and monomorphous alpha (18 index cases) have been included in the study, as well as the first degree relatives of the index cases, thus providing a clinical classification into four groups. The proposed method provides an automatic and reliable classification algorithm using discriminant and cluster analysis. The relation between such an automatized classification and clinical classification schemes is investigated. In particular, the inheritance of the low voltage EEG, the question on sex differences and the question of a simple Mendelian mechanism had been examined. The method of random splittings had been applied for discriminant and cluster analysis. Our findings can be summarized as follows: (1) except for the monomorphous alpha EEG group, the clinical classification shows rather marginal separation (discriminating performance 60% to 75%), while a new and more reliable grouping scheme improves the discriminating performance up to 87% to 91%. The latter scheme leads to the concept of personal channel pattern (PCP) and was compared to the clinical classification scheme by means of contingency tables; (2) only a weak correlation between the clinically and PCP-based groups could be found (Cramér Index: 0.27). Accordingly, we continued to investigate the extent to which the proposed EEG classification scheme can nevertheless explain the genetic mechanisms apparently involved in the low voltage EEG. We thus considered the role of sex differences manifest in our proposed new grouping scheme; (3) males occurred more frequently in the new group 3 and females more frequently in the new group 1. In this regard, a much better correlation of the new groups between mothers and children than between fathers and children was observed; and (4) with help of our new PCP scheme, we have been able to reproduce a simple two gene Mendelian scheme to explain inheritance of the clinical low voltage EEG group. In this PCP-based scheme, the low voltage property does not occur when dominance of a certain gene (called gene A) is absent.

Adult↗

Oblique decision trees for spatial pattern detection: optimal algorithm and application to malaria risk.

BACKGROUND: In order to detect potential disease clusters where a putative source cannot be specified, classical procedures scan the geographical area with circular windows through a specified grid imposed to the map. However, the choice of the windows' shapes, sizes and centers is critical and different choices may not provide exactly the same results. The aim of our work was to use an Oblique Decision Tree model (ODT) which provides potential clusters without pre-specifying shapes, sizes or centers. For this purpose, we have developed an ODT-algorithm to find an oblique partition of the space defined by the geographic coordinates. METHODS: ODT is based on the classification and regression tree (CART). As CART finds out rectangular partitions of the covariate space, ODT provides oblique partitions maximizing the interclass variance of the independent variable. Since it is a NP-Hard problem in RN, classical ODT-algorithms use evolutionary procedures or heuristics. We have developed an optimal ODT-algorithm in R2, based on the directions defined by each couple of point locations. This partition provided potential clusters which can be tested with Monte-Carlo inference. We applied the ODT-model to a dataset in order to identify potential high risk clusters of malaria in a village in Western Africa during the dry season. The ODT results were compared with those of the Kulldorff' s SaTScan. RESULTS: The ODT procedure provided four classes of risk of infection. In the first high risk class 60%, 95% confidence interval (CI95%) [52.22-67.55], of the children was infected. Monte-Carlo inference showed that the spatial pattern issued from the ODT-model was significant (p < 0.0001). Satscan results yielded one significant cluster where the risk of disease was high with an infectious rate of 54.21%, CI95% [47.51-60.75]. Obviously, his center was located within the first high risk ODT class. Both procedures provided similar results identifying a high risk cluster in the western part of the village where a mosquito breeding point was located. CONCLUSION: ODT-models improve the classical scanning procedures by detecting potential disease clusters independently of any specification of the shapes, sizes or centers of the clusters.

Africa, Western↗

Production of lovastatin examined by an integrated approach based on chemometrics and DOSY-NMR.

Microbial secondary metabolites are one of the sources of therapeutic molecules in the pharmaceutical industry. Product quality and high yields of secondary metabolites are the main goals for the commercial success of a fermentation process. Our novel approach was based on the decision-tree algorithm to determine the key variables correlated with the process outcome and on DOSY-NMR to identify both co-metabolites and impurities, and it improves fermentation systems and speeds up bioprocess development. The approach has been validated in the case of lovastatin production from Aspergillus terreus.

Algorithms↗

Assigning new GO annotations to protein data bank sequences by combining structure and sequence homology.

Accompanying the discovery of an increasing number of proteins, there is the need to provide functional annotation that is both highly accurate and consistent. The Gene Ontology (GO) provides consistent annotation in a computer readable and usable form; hence, GO annotation (GOA) has been assigned to a large number of protein sequences based on direct experimental evidence and through inference determined by sequence homology. Here we show that this annotation can be extended and corrected for cases where protein structures are available. Specifically, using the Combinatorial Extension (CE) algorithm for structure comparison, we extend the protein annotation currently provided by GOA at the European Bioinformatics Institute (EBI) to further describe the contents of the Protein Data Bank (PDB). Specific cases of biologically interesting annotations derived by this method are given. Given that the relationship between sequence, structure, and function is complicated, we explore the impact of this relationship on assigning GOA. The effect of superfolds (folds with many functions) is considered and, by comparison to the Structural Classification of Proteins (SCOP), the individual effects of family, superfamily, and fold.

Algorithms↗

A surface of minimum area metric for the structural comparison of proteins.

A new method for comparing protein structures, based on a minimal surface metric, is developed. A virtual polypeptide backbone is created by joining consecutive C alpha atoms in a protein structure. The minimal surface between the virtual backbones of two proteins (the Area Functional) is determined numerically using an iterative triangulation strategy. The first protein is then rotated and translated in space until the smallest minimal surface is obtained. Such a technique yields the optimal structural superposition between two protein segments. It requires no initial sequence alignment, is relatively insensitive to insertions and deletions, and obviates the need to select a gap penalty. The optimal minimal area can then be converted to the Area-C alpha distance, measured in angstroms, to determine the structural similarity. This technique has been applied to a large class of proteins and is able to detect not only small-scale differences between closely related proteins but also large-scale topological similarities between evolutionary unrelated proteins that lack any obvious sequence homology. To measure the similarity between structurally dissimilar proteins, an additional measure (the Fit Comparison) is developed. This is a scale-invariant measure of a structural similarity that is useful for determining topological similarities between dissimilar proteins with unrelated sequences.

Algorithms↗

Freeway safety as a function of traffic flow.

In this paper, we present evidence of strong relationships between traffic flow conditions and the likelihood of traffic accidents (crashes), by type of crash. Traffic flow variables are measured using standard monitoring devices such as single inductive loop detectors. The key traffic flow elements that affect safety are found to be mean volume and median speed, and temporal variations in volume and speed, where variations need to be distinguished by freeway lane. We demonstrate how these relationships can form the basis for a tool that monitors the real-time safety level of traffic flow on an urban freeway. Such a safety performance monitoring tool can also be used in cost-benefit evaluations of projects aimed at mitigating congestion, by comparing the levels of safety of traffic flows patterns before and after project implementation.

Accidents, Traffic↗

Gene expression in the developing rat mandible: a gene array study.

To analyse the molecular events that occur in the developing mandible, gene arrays containing probes for 1176 known genes were used. Total RNA was extracted from the mandibles of 1- and 6-day-old rats. Radiolabeled probes were then synthesised and used to probe the DNA arrays. Of the 1176 genes examined, 306 were detectable, and the latter were analyzed by bioinformatics algorithms. K-means clustering grouped 72 genes into Up, 56 genes into Down and 178 genes into NO change. A large number of genes related to cell receptors (by ligands) were grouped into the Down cluster. Gene array technology appears to be a useful tool for studying the complex process of mandibular development.

Animals↗