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HykGene: a hybrid approach for selecting marker genes for phenotype classification using microarray gene expression data.

MOTIVATION: Recent studies have shown that microarray gene expression data are useful for phenotype classification of many diseases. A major problem in this classification is that the number of features (genes) greatly exceeds the number of instances (tissue samples). It has been shown that selecting a small set of informative genes can lead to improved classification accuracy. Many approaches have been proposed for this gene selection problem. Most of the previous gene ranking methods typically select 50-200 top-ranked genes and these genes are often highly correlated. Our goal is to select a small set of non-redundant marker genes that are most relevant for the classification task. RESULTS: To achieve this goal, we developed a novel hybrid approach that combines gene ranking and clustering analysis. In this approach, we first applied feature filtering algorithms to select a set of top-ranked genes, and then applied hierarchical clustering on these genes to generate a dendrogram. Finally, the dendrogram was analyzed by a sweep-line algorithm and marker genes are selected by collapsing dense clusters. Empirical study using three public datasets shows that our approach is capable of selecting relatively few marker genes while offering the same or better leave-one-out cross-validation accuracy compared with approaches that use top-ranked genes directly for classification. AVAILABILITY: The HykGene software is freely available at http://www.cs.dartmouth.edu/~wyh/software.htm CONTACT: wyh@cs.dartmouth.edu SUPPLEMENTARY INFORMATION: Supplementary material is available from http://www.cs.dartmouth.edu/~wyh/hykgene/supplement/index.htm.

Algorithms↗

Evolution of the electronic structure of Be clusters.

Using a modified symbiotic genetic algorithm approach and many-body interatomic potential derived from first principles, we have calculated equilibrium geometries and binding energies of the ground-state and low-lying isomers of Be clusters containing up to 41 atoms. Molecular-dynamics study was also carried out to study the frequency of occurrence of the various geometrical isomers as these clusters are annealed during the simulation process. For a selected group of these clusters, higher-energy isomers were more often found than their ground-state structures due to large catchment areas. The accuracy of the above ground-state geometries and their corresponding binding energies were verified by carrying out separate ab initio calculations based on molecular-orbital approach and density-functional theory with generalized gradient approximation for exchange and correlation. The atomic orbitals were represented by a Gaussian 6-311G** basis, and the geometry optimization was carried out using the GAUSSIAN 98 code without any symmetry constraint. While the ground-state geometries and their corresponding binding energies obtained from ab initio calculations do not differ much from those obtained using the molecular-dynamics approach, the relative stability of the clusters and the energy gap between the highest occupied and the lowest unoccupied molecular orbitals show significant differences. The energy gaps, calculated using the density-functional theory, show distinct shell closure effects, namely, sharp drops in their values for Be clusters containing 2, 8, 20, 34, and 40 electrons. While these features may suggest that small Be clusters behave free-electron-like and, hence, are metallic, the evolution of the structure, binding energies, coordination numbers, and nearest-neighbor distances do not show any sign of convergence towards the bulk value. We also conclude that molecular-dynamics simulation based on many-body interatomic potentials may not always give the correct picture of the evolution of the structure and energetics of clusters although they may serve as a useful tool for obtaining starting geometries by efficiently searching a large part of the phase space.

Journal Article↗

Hierarchical clustering to measure connectivity in fMRI resting-state data.

Low frequency oscillations, which are temporally correlated in functionally related brain regions, characterize the mammalian brain, even when no explicit cognitive tasks are performed. Functional connectivity MR imaging is used to map regions of the resting brain showing synchronous, regional and slow fluctuations in cerebral blood flow and oxygenation. In this study, we use a hierarchical clustering method to detect similarities of low-frequency fluctuations. We describe one measure of correlations in the low frequency range for classification of resting-state fMRI data. Furthermore, we investigate the contribution of motion and hardware instabilities to resting-state correlations and provide a method to reduce artifacts. For all cortical regions studied and clusters obtained, we quantify the degree of contamination of functional connectivity maps by the respiratory and cardiac cycle. Results indicate that patterns of functional connectivity can be obtained with hierarchical clustering that resemble known neuronal connections. The corresponding voxel time series do not show significant correlations in the respiratory or cardiac frequency band.

Adult↗

A short educational intervention on communication skills improves the quality of screening for Chlamydia in GPs in Belgium: a cluster randomised controlled trial.

An accurate algorithm for screening for chlamydial infections is available in general practice, but GPs experience numerous barriers to sexually transmitted infections (STI) counselling. In this study we assessed if a short educational package, under the form of a commented video footage on communication skills, was helpful in implementing the screening strategy. A cluster randomised controlled trial was carried out in 36 general practitioners in Antwerp, Belgium. Main outcome measures were: number of patients included in the risk assessment, number of patients tested, and proportion of appropriately tested patients. The results show that GPs in the intervention group did not include more patients overall, but that the quality of the screening process was significantly better (81.6% versus 56.2% appropriate tests, P = 0.02). Conclusively, GPs who participated in a short educational package on communication skills, selected eligible candidates for screening more accurately and decreased the risk of overscreening.

Adult↗

DSM-III-R as a taxonomy. A cluster analysis of diagnoses and symptoms.

While there have been many applications of cluster analysis in psychiatric classification research, there are no studies in which cluster analysis is used to discover the taxonomic structure implicit in the DSM-III itself. In order to do so, the symptom index in the DSM-III-R manual was summarized in a two-way matrix of disorders by symptoms and then analyzed using a hierarchical classes model and companion algorithm (HICLAS) that permits overlap among classes. A novel feature of this model is that superordinate-subordinate relationships among diagnostic and symptom classes are explicitly represented. The HICLAS analysis revealed that there are several discrete symptom classes in DSM-III-R and that many psychiatric disorders can be modeled as combinations of one or more of these classes. The disorders associated with these symptom classes tend to fit the hierarchical classes model relatively well, particularly the mood disorders and the psychotic disorders. However, disorders such as adjustment, personality, and sexual disorder fit the model poorly or not at all. The results are in line with the conjecture that the taxonomic model implicit in DSM-III-R is a hybrid of discrete symptom classes and some other structure, perhaps a dimensional one.

Algorithms↗

HCNet: a database of heart and calcium functional network.

SUMMARY: The Heart and Calcium functional Network (HCNet) database is a collection of functional gene modules calculated from the microarray data compendium available from the GEO database. It is a specialized database designed to assist experimentalists for cardiac calcium signaling research by providing the pre-calculated gene clusters and their potential correlation network in heart. In the current release of HCNet, 57 functional modules from 786 target genes obtained by a bi-clustering analysis of 381 microarray datasets are available. Detailed information of the clusters such as expression profiles, network diagrams is provided in two categories, heart-specific genes and heart-specific genes along with calcium toolkit genes. Overrepresented gene ontological categories and transcription factors in each cluster are also provided to infer the biological implications of the detected functional modules. AVAILABILITY: HCNet is available at http://sbrg2.gist.ac.kr/hcnet.

Algorithms↗

Symptom clustering in advanced cancer.

A major goal of palliative medicine is to control symptoms that interfere with quality of life. Identification of symptoms that occur together (cluster) may aid in symptom management, resulting in greater therapeutic benefit to the patient. An analysis of 25 symptoms from 922 patients with advanced cancer was undertaken to determine if symptom clusters could be identified. Cluster analysis was done using an agglomerative hierarchical method with average linkage; the absolute value of the correlation between pairs of symptoms was used as the measure of similarity. A correlation of >or=0.68 was used to define the final clusters. Seven clusters were identified: (1) fatigue: anorexia-cachexia; (2) neuropsychological; (3) upper gastrointestinal; (4) nausea and vomiting; (5) aerodigestive; (6) debility; (7) pain. Recognition of symptom clusters should help understand symptom pathophysiology and target therapies that perhaps can be used to relieve multiple symptoms in that cluster. This could result in improved quality of life for patients with advanced cancer and perhaps reduce polypharmacy, lessen drug side effects, and have pharmacoeconomic benefits.

Adolescent↗

Aeromonas hydrophila: variability in biochemical characteristics of environmental isolates.

A total of 161 strains, including 144 aeromonads, of which 100 had been isolated from water and sediment samples from the Chesapeake Bay, five clinical and 33 Anacostia River isolates of Aeromonas hydrophila, six Aeromonas sobria, and ten reference cultures were examined in a numerical taxonomy study in which each of the strains were examined for 56 unit characters. Similarity between strains was computed using the simple matching (SSM) and Jaccard (SJ) coefficients. The strains were clustered by unweighted average linkage and single linkage algorithms. Results of all analyses yielded similar clusterings of strains. Of the 161 strains included in the study, 148 were recovered in seven major clusters. A large cluster of Aeromonas hydrophila yielded two sub-clusters. From the results of the taxonomic analysis it is concluded that several biovars of Aeromonas hydrophila can be isolated from the aquatic environment, but geographical or site specific distribution of the biovars could not be detected.

Aeromonas hydrophila↗

Microarrays and cell cycle transcription in yeast.

Microarrays have been used to characterize gene expression through the yeast cell cycle. Computational methods have been applied to the microarray data to identify coregulated clusters of genes, and motif-finding algorithms have found promoter elements characteristic of each cluster. The functional relevance of these promoter elements can be tested using chromatin immunoprecipitation, additional microarrays and other molecular techniques. The yeast forkhead proteins have been successfully identified as cell cycle transcription factors for an important cluster of genes by this and other approaches.

Cell Cycle↗

Ant-based clustering and topographic mapping.

Ant-based clustering and sorting is a nature-inspired heuristic first introduced as a model for explaining two types of emergent behavior observed in real ant colonies. More recently, it has been applied in a data-mining context to perform both clustering and topographic mapping. Early work demonstrated some promising characteristics of the heuristic but did not extend to a rigorous investigation of its capabilities. We describe an improved version, called ATTA, incorporating adaptive, heterogeneous ants, a time-dependent transporting activity, and a method (for clustering applications) that transforms the spatial embedding produced by the algorithm into an explicit partitioning. ATTA is then subjected to the most rigorous experimental evaluation of an ant-based clustering and sorting algorithm undertaken to date: we compare its performance with standard techniques for clustering and topographic mapping using a set of analytical evaluation functions and a range of synthetic and real data collections. Our results demonstrate the ability of ant-based clustering and sorting to automatically identify the number of clusters inherent in a data collection, and to produce high quality solutions; indeed, we show that it is particularly robust for clusters of differing sizes and for overlapping clusters. The results obtained for topographic mapping are, however, disappointing. We provide evidence that the solutions generated by the ant algorithm are barely topology-preserving, and we explain in detail why results have--in spite of this--been misinterpreted (much more positively) in previous research.

Algorithms↗

Application of minimal spanning trees in glioma grading--a CLIPPER program for the calculation and construction of minimal spanning trees.

We present a CLIPPER program for the calculation and graphical representation of minimal spanning trees (MST) which is available on request on diskette from the authors. The MST are a useful parameter for structural cluster detection. They can be applied to grading problems in tumour biology. We present and discuss the applicability of MST by an example from the field of astrocytoma grading.

Algorithms↗

Assessment of hierarchical clustering methodologies for proteomic data mining.

Hierarchical clustering methodology is a powerful data mining approach for a first exploration of proteomic data. It enables samples or proteins to be grouped blindly according to their expression profiles. Nevertheless, the clustering results depend on parameters such as data preprocessing, between-profile similarity measurement, and the dendrogram construction procedure. We assessed several clustering strategies by calculating the F-measure, a widely used quality metric. The combination, on logged matrix, of Pearson correlation and Ward's methods for data aggregation is among the best clustering strategies, at least with the data sets we studied. This study was carried out using PermutMatrix, a freely available software derived from transcriptomics.

Algorithms↗

Prediction of the main cortical areas and connections involved in the tactile function of the visual cortex by network analysis.

We explored the cortical pathways from the primary somatosensory cortex to the primary visual cortex (V1) by analysing connectional data in the macaque monkey using graph-theoretical tools. Cluster analysis revealed the close relationship of the dorsal visual stream and the sensorimotor cortex. It was shown that prefrontal area 46 and parietal areas VIP and 7a occupy a central position between the different clusters in the visuo-tactile network. Among these structures all the shortest paths from primary somatosensory cortex (3a, 1 and 2) to V1 pass through VIP and then reach V1 via MT, V3 and PO. Comparison of the input and output fields suggested a larger specificity for the 3a/1-VIP-MT/V3-V1 pathways among the alternative routes. A reinforcement learning algorithm was used to evaluate the importance of the aforementioned pathways. The results suggest a higher role for V3 in relaying more direct sensorimotor information to V1. Analysing cliques, which identify areas with the strongest coupling in the network, supported the role of VIP, MT and V3 in visuo-tactile integration. These findings indicate that areas 3a, 1, VIP, MT and V3 play a major role in shaping the tactile information reaching V1 in both sighted and blind subjects. Our observations greatly support the findings of the experimental studies and provide a deeper insight into the network architecture underlying visuo-tactile integration in the primate cerebral cortex.

Algorithms↗

Three-dimensional classification of spinal deformities using fuzzy clustering.

STUDY DESIGN: A prospective study of a large set of three-dimensional (3D) reconstructions of spinal deformities in adolescent idiopathic scoliosis (AIS). OBJECTIVES: To determine the value of fuzzy clustering techniques to automatically detect clinically relevant 3D curve patterns within this set of 3D spine models. SUMMARY OF BACKGROUND DATA: Classification is important for the assessment of AIS and has been mainly used to guide surgical treatment. Current classification systems are based on visual curve pattern identification using two-dimensional radiologic measurements but remain controversial because of their low interobserver and intraobserver reliability. A clinically useful 3D classification remains to be found. METHODS: An unsupervised learning algorithm, fuzzy k-means clustering, was applied on 409 3D spine models. Analysis of data distribution using clinical parameters was performed by studying similar curve patterns, near each cluster center identified. RESULTS: The algorithm determined that the entire sample of models could be segmented in five easily differentiated curve patterns similar to those of the Lenke and King classifications. Furthermore, a system with 12 classes made possible the identification of subpatterns of spinal deformity with true 3D components. CONCLUSIONS: Automatic and clinically relevant 3D classification of AIS is possible using an unsupervised learning algorithm. This approach can now be used to build a relevant 3D classification of AIS using appropriate key features of 3D models selected by a panel of expert spinal deformity surgeons.

Adolescent↗

A gait nomogram used with fuzzy clustering to monitor functional status of children and young adults with cerebral palsy.

We have developed a gait nomogram based on dynamic similarity to characterize and compare neuromuscular function. We used temporal-distance data based on 669 normal participants (age range 5 to 98 years), and 78 children and young adults with spastic diplegia (43 males, 35 females; mean age 10 y 8 mo, standard deviation 3 y 11 mo, range 5 to 20 y), all of whom were independent ambulators. A new statistical algorithm known as fuzzy clustering was implemented and five cluster centres were identified, each representing distinct walking strategies adopted by children with cerebral palsy. Using just three easily obtained parameters--leg length in metres, stride length in metres, and cadence in steps per minute--our program calculates a child's dimensionless step length and step frequency, generates the individual's membership values for each of the five clusters, and plots the gait nomogram. The clinical utility of our approach has been demonstrated for two test participants with spastic diplegia, using pre- and postoperative data (one neurosurgical and one orthopaedic), where changes in membership of the five clusters provide objective measures of improvement in their neuromuscular function.

Adolescent↗

Fuzzy and crisp set-theoretic-based classification of health and disease. A qualitative and quantitative comparison.

Conventional cluster analyses of patient populations are intended to assist in the identification and characterization of groups that may represent etiological or pathological subtypes within a particular disease class. These methods have been criticized as being insensitive to subtle patient differences, which may be masked as a result of the all-or-nothing concept of cluster membership intrinsic to crisp set-theoretic-based grouping algorithms. As an alternative to conventional clustering procedures, several investigators have studied the use of fuzzy classification methods. In general, these measure a patient's clinical status in terms of a real number defined on the closed unit interval, reflecting the extent or degree to which a particular grouping entity characterizes the patient. This paper compares and contrasts the applications of crisp and fuzzy set-theoretic-based clustering procedures to a set of data describing the cognitive and intellectual functioning of a group of subjects participating in a longitudinal study of aging. Emphasis is placed on both qualitative and quantitative aspects corresponding, respectively, to the clinical interpretation of cluster definitions, and the robustness or sensitivity of the classification procedures to changes in patient profiles over time. The fuzzy set-theoretic-based model was found to be more sensitive to changes in subject level of functioning over time, to provide superior quantitative protrayals of patterns of aging, and to reflect properties of the aging process derived from other research.

Aged↗

A method for comparing multiple bacterial community structures from 16S rDNA clone library sequences.

Culture-independent approaches, based on 16S rDNA sequences, are extensively used in modern microbial ecology. Sequencing of the clone library generated from environmental DNA has advantages over fingerprint-based methods, such as denaturing gradient gel electrophoresis, as it provides precise identification and quantification of the phylotypes present in samples. However, to date, no method exists for comparing multiple bacterial community structures using clone library sequences. In this study, an automated method to achieve this has been developed, by applying pair wise alignment, hierarchical clustering and principle component analysis. The method has been demonstrated to be successful in comparing samples from various environments. The program, named CommCluster, was written in JAVA, and is now freely available, at http://chunlab.snu.ac.kr/commcluster/.

Algorithms↗

Comprehensive aligned sequence construction for automated design of effective probes (CASCADE-P) using 16S rDNA.

MOTIVATION: Prokaryotic organisms have been identified utilizing the sequence variation of the 16S rRNA gene. Variations steer the design of DNA probes for the detection of taxonomic groups or specific organisms. The long-term goal of our project is to create probe arrays capable of identifying 16S rDNA sequences in unknown samples. This necessitated the authentication, categorization and alignment of the >75 000 publicly available '16S' sequences. Preferably, the entire process should be computationally administrated so the aligned collection could periodically absorb 16S rDNA sequences from the public records. A complete multiple sequence alignment would provide a foundation for computational probe selection and facilitates microbial taxonomy and phylogeny. RESULTS: Here we report the alignment and similarity clustering of 62 662 16S rDNA sequences and an approach for designing effective probes for each cluster. A novel alignment compression algorithm, NAST (Nearest Alignment Space Termination), was designed to produce the uniform multiple sequence alignment referred to as the prokMSA. From the prokMSA, 9020 Operational Taxonomic Units (OTUs) were found based on transitive sequence similarities. An automated approach to probe design was straightforward using the prokMSA clustered into OTUs. As a test case, multiple probes were computationally picked for each of the 27 OTUs that were identified within the Staphylococcus Group. The probes were incorporated into a customized microarray and were able to correctly categorize Staphylococcus aureus and Bacillus anthracis into their correct OTUs. Although a successful probe picking strategy is outlined, the main focus of creating the prokMSA was to provide a comprehensive, categorized, updateable 16S rDNA collection useful as a foundation for any probe selection algorithm.

Algorithms↗