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PubMed1995

Extracting knowledge from large medical databases: an automated approach.

Tools which can uncover patterns in patients' records and then make predictions based on that knowledge are and will continue to be high priority in many medical informatics groups. These tools are impacting the performance of outcome studies by discovering patterns which can then be verified with standard statistical tools. This paper demonstrates INC2.5, a general classification system, as a tool for assisting physicians in the decision making process. INC2.5 gathers information from patient records and builds a decision tree which is used to assist physicians in predicting the outcome of new patients. The decision tree will also reveal any patterns which the system found in the data. Successful results of such a system can be used to enhance outcome studies as well as to spread clinical information to areas with fewer resources.

Algorithms↗

PubMed2000

Co-evolution of proteins with their interaction partners.

The divergent evolution of proteins in cellular signaling pathways requires ligands and their receptors to co-evolve, creating new pathways when a new receptor is activated by a new ligand. However, information about the evolution of binding specificity in ligand-receptor systems is difficult to glean from sequences alone. We have used phosphoglycerate kinase (PGK), an enzyme that forms its active site between its two domains, to develop a standard for measuring the co-evolution of interacting proteins. The N-terminal and C-terminal domains of PGK form the active site at their interface and are covalently linked. Therefore, they must have co-evolved to preserve enzyme function. By building two phylogenetic trees from multiple sequence alignments of each of the two domains of PGK, we have calculated a correlation coefficient for the two trees that quantifies the co-evolution of the two domains. The correlation coefficient for the trees of the two domains of PGK is 0. 79, which establishes an upper bound for the co-evolution of a protein domain with its binding partner. The analysis is extended to ligands and their receptors, using the chemokines as a model. We show that the correlation between the chemokine ligand and receptor trees' distances is 0.57. The chemokine family of protein ligands and their G-protein coupled receptors have co-evolved so that each subgroup of chemokine ligands has a matching subgroup of chemokine receptors. The matching subfamilies of ligands and their receptors create a framework within which the ligands of orphan chemokine receptors can be more easily determined. This approach can be applied to a variety of ligand and receptor systems.

Chemokines↗

PubMed1986

Mitochondrial DNA evolution in the melanogaster species subgroup of Drosophila.

Detailed restriction maps (40 cleavage sites on average) of mitochondrial DNAs (mtDNAs) from the eight species of the melanogaster species subgroup of Drosophila were established. Comparison of the cleavage sites allowed us to build a phylogenetic tree based on the matrix of nucleotide distances and to select the most parsimonious network. The two methods led to similar results, which were compared with those in the literature obtained from nuclear characters. The three chromosomally homosequential species D. simulans, D. mauritiana, and D. sechellia are mitochondrially very related, but exhibit complex phylogenetic relationships. D. melanogaster is their closest relative, and the four species form a monophyletic group (the D. melanogaster complex), which is confirmed by the shared unusual length of their mt genomes (18-19 kb). The other four species of the subgroup (D. yakuba, D. teissieri, D. erecta, and D. orena) are characterized by a much shorter mt genome (16-16.5 kb). The monophyletic character of the D. yakuba complex, however, is questionable. Two species of this complex, D. yakuba and D. teissieri, are mitochondrially indistinguishable (at the level of our investigation) in spite of their noticeable allozymic and chromosomal divergence. Finally, mtDNA distances were compared with the nuclear-DNA distances thus far established. These sequences seem to evolve at rather similar rates, the mtDNA rate being barely double that of nuclear DNA.

Animals↗

PubMed2000

Computer-assisted decision analysis in orthopedics: resurfacing the patella in total knee arthroplasty as an example.

The purpose of the present study was to illustrate the use of computer-assisted decision analysis in making decisions in the field of orthopaedic surgery, using the choice between resurfacing and not resurfacing the patella in total knee arthroplasty as an example. We used a decision analysis technique based on probability theory and on Bayesian logic, with the help of an especially developed computer software. The process involves building a decision tree, searching for probabilities and utilities in the literature, folding back the tree to compute the baseline result, and running sensitivity analyses. Our literature search provided 26 useful articles, only 3 of which were randomized controlled trials. In the baseline analysis, both options were rated similarly, with resurfacing the patella faring slightly better. Sensitivity analyses revealed that not resurfacing becomes the procedure of choice if the probability of postoperative anterior knee pain with an unresurfaced patella falls below 14%, or if the probability of having pain with a resurfaced patella rises above 8% or if the utility of patellar implant failure falls below 80% of the utility of a perfect health state. Computer-assisted decision analysis is a promising, evidence-based tool to assist clinical decision making in orthopaedic surgery. However, its validity is limited by the poor quality of data found in the orthopaedic literature, especially the scarcity of randomized controlled trials.

Arthroplasty, Replacement, Knee↗

PubMed2005

Discrete serum protein signatures discriminate between human retrovirus-associated hematologic and neurologic disease.

The human T-cell leukemia virus type I (HTLV-I) is the causative agent for adult T-cell leukemia (ATL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Approximately 5% of infected individuals will develop either disease and currently there are no diagnostic tools for early detection or accurate assessment of disease state. We have employed high-throughput expression profiling of serum proteins using mass spectrometry to identify protein expression patterns that can discern between disease states of HTLV-I-infected individuals. Our study group consisted of 42 ATL, 50 HAM/TSP, and 38 normal controls. Spectral peaks corresponding to peptide ions were generated from MS-TOF data. We applied Classification and Regression Tree analysis to build a decision algorithm, which achieved 77% correct classification rate across the three groups. A second cohort of 10 ATL, 10 HAM and 10 control samples was used to validate this result. Linear discriminate analysis was performed to verify and visualize class separation. Affinity and sizing chromatography coupled with tandem mass spectrometry was used to identify three peaks specifically overexpressed in ATL: an 11.7 kDa fragment of alpha trypsin inhibitor, and two contiguous fragments (19.9 and 11.9 kDa) of haproglobin-2. To the best of our knowledge, this is the first application of protein profiling to distinguish between two disease states resulting from a single infectious agent.

Adolescent↗

PubMed1998

A new regimen for starting warfarin therapy in out-patients.

AIMS: Oral anticoagulation is increasingly used in elderly patients with atrial fibrillation to prevent embolic phenomena. The use of anticoagulants in this population is prophylactic rather than therapeutic and so there is no urgency to establish anticoagulation within the desired therapeutic range. The aim of the study was to develop an out-patient regimen for initiation of oral anticoagulation with warfarin which requires only weekly monitoring of the International Normalized Ratio (INR). METHODS: The study was undertaken in two phases. In the first phase, factors which predict the final maintenance dosage of warfarin were defined and used to build a decision tree and dosage algorithm. In the second study the algorithm was tested. Patients were given 2 mg warfarin daily for 2 weeks and the INR at this time was used to predict the maintenance dose. Patients then attended for weekly measurements of the INR until steady state had been reached. Dosage adjustments were not made unless the INR was >4.0 or <1.5 for 2 consecutive weeks. The accuracy of the prediction was measured by calculating the mean INR of weeks 6-8 and the number of patients in the target range 2.0-3.0 was determined. RESULTS: One hundred and seven consecutive out-patients (mean age 70 years range 64-86) completed the first study. The age, sex, height, weight, alcohol intake, number of cigarettes smoked, concomitant medication, clinical evidence of right heart failure, liver failure, abnormalities in liver enzyme estimations, baseline INR and INR after 2 weeks of 2 mg warfarin daily were used in a polytomous logistic regression analysis with stepwise inclusion of factors to determine which factors influenced the eventual maintenance dosage of warfarin. The INR after 2 weeks of 2 mg warfarin therapy predicted 70% of the variability of the maintenance dose. Of other factors only the sex of the patient had a large enough effect to be included in the prediction algorithm. One hundred and six patients (mean age 71 years range 50-85 years) completed the second study. Only one patient needed a dose adjustment in the first 2 weeks of warfarin 2 mg daily (INR 4.4). Overall, 60% patients were in the narrow target range (INR 2.0-3.0) at steady state. In five patients the INR was >4.0 at any visit after the second week and needed dosage adjustment. In four patients the INR was <1.5 at steady state. CONCLUSIONS: We have developed a method of predicting the maintenance dose of warfarin in an elderly population based on the INR after 2 weeks of warfarin 2 mg daily, and the sex of the patient. This is a safe and convenient way of initiating warfarin therapy as an out-patient which requires only weekly INR checks.

Aged↗

PubMed2002

Utility of low-copy nuclear gene sequences in plant phylogenetics.

Low-copy nuclear genes in plants are a rich source of phylogenetic information. They hold a great potential to improve the robustness of phylogenetic reconstruction at all taxonomic levels, especially where universal markers such as cpDNA and nrDNA are unable to generate strong phylogenetic hypotheses. Low-copy nuclear genes, however, remain underused in plant phylogenetic studies due to practical and theoretical complications in unraveling the evolutionary dynamics of nuclear gene families. The lack of the universal markers or universal PCR primers of low-copy nuclear genes has also hampered their phylogenetic utility. It has recently become clear that low-copy nuclear genes are particularly helpful in resolving close interspecific relationships and in reconstructing allopolyploidization in plants. Gene markers that are widely, if not universally, useful have begun to emerge. Although utilizing low-copy nuclear genes usually requires extra lab work such as designing PCR primers, PCR-cloning, and/or Southern blotting, rapid accumulation of gene sequences in the databases and advances in cloning techniques have continued to make such studies more feasible. With the growing number of theoretical studies devoted to the gene tree and species tree problem, a solid foundation for reconstructing complex plant phylogenies based on multiple gene trees began to build. It is also realized increasingly that fast evolving introns of the low-copy nuclear genes will provide much needed phylogenetic information around the species boundary and allow us to address fundamental questions concerning processes of plant speciation. Phylogenetic and molecular evolutionary analyses of developmentally important genes will add a new dimension to systematic and evolutionary studies of plant diversity.

Cell Nucleus↗

PubMed2004

Glutathione pathway genes and lung cancer risk in young and old populations.

Multiple enzymes with overlapping functions and shared substrates in the glutathione (GSH) metabolic pathway have been associated with host susceptibility to tobacco smoke carcinogens and in lung cancer etiology. However, few studies have investigated the differing and interacting roles of GSH pathway enzymes with tobacco smoke exposure on lung cancer risk in young (<50 years of age) and old (>80 years of age) populations. Between 1997 and 2001, 237 primary lung cancer patients (170 young, 67 old) and 234 controls (165 young, 69 old) were enrolled at the Mayo Clinic. Using PCR amplification of genomic DNA, polymorphic markers for gammaGCS, GPX1, GSTP1 (I105V and A114V), GSTM1 and GSTT1 were genotyped. Recursive partitioning and logistic regression models were used to build binary classification trees and to estimate odds ratios (OR) and 95% confidence intervals for each splitting factor. For the young age group, cigarette smoking had the greatest association with lung cancer (OR = 3.3). For never smokers, the dividing factors of recursive partitioning were GSTT1 (OR = 1.7), GPX1 (OR = 0.6) and GSTM1 (OR = 4.3). For the old age group, smoking had the greatest association with lung cancer (OR = 3.6). For smokers, the dividing factors were GPX1 (OR = 3.3) and GSTP1 (I105V) (OR = 4.1). Results from logistic regression analyses supported the results from RPART models. GSH pathway genes are associated with lung cancer development in young and old populations through differing interactions with cigarette smoking and family history. Carefully evaluating multiple levels of gene-environment and gene-gene interactions is critical in assessing lung cancer risk.

Acyltransferases↗

PubMed2006

Cost-effectiveness of neonatal ECG screening for the long QT syndrome.

AIMS: A significant number of preventable cardiac deaths in infancy and childhood are due to long QT syndrome (LQTS) and to unrecognized neonatal congenital heart diseases (CHDs). Both carry a serious risk for avoidable mortality and morbidity but effective treatments exist to prevent lethal arrhythmias or to allow early surgical correction before death or irreversible cardiac damage. As an electrocardiogram (ECG) allows recognition of LQTS and of some of the CHDs that have escaped medical diagnosis, and as LQTS also contributes to sudden infant death syndrome, we have analysed the cost-effectiveness of a nationwide programme of neonatal ECG screening. Our primary analysis focused on LQTS alone; a secondary analysis focused on the possibility of identifying some CHDs also. METHODS AND RESULTS: A decision analysis approach was used, building a decision tree for the strategies 'screening'-'no screening'. Markov processes were used to simulate the natural or clinical histories of the patients. To assess the impact of potential errors in the estimates of the model parameters, a Monte Carlo sensitivity analysis was performed by varying all baseline values by +/-30%. Incremental cost-effectiveness analysis for the primary analysis shows that with the screening programme, the cost per year of life saved is very low: 11,740 euro. The cost for saving one entire life of 70 years would be 820,000 euro. Even by varying model parameters by +/-30%, the cost per year of life saved remains between 7400 euro and 20,400 euro. These figures define 'highly cost-effective' screening programmes. The secondary analysis provides even more cost-effective results. CONCLUSION: A programme of neonatal ECG screening performed in a large European country is cost-effective. An ECG performed in the first month of life will allow the early identification of still asymptomatic infants with LQTS and also of infants with some correctable CHDs not recognized by routine neonatal examinations. Appropriate therapy will prevent unnecessary deaths in infants, children, and young adults.

Cohort Studies↗

PubMed2003

Improvements to CluSTr: the database of SWISS-PROT+TrEMBL protein clusters.

The CluSTr database (http://www.ebi.ac.uk/clustr/) offers an automatic classification of SWISS-PROT+TrEMBL proteins into groups of related proteins. The clustering is based on analysis of all pair-wise sequence comparisons between proteins using the Smith-Waterman algorithm. The analysis, carried out on different levels of protein similarity, yields a hierarchical organization of clusters. Information about domain content of the clustered proteins is provided via the InterPro resource. The introduced InterPro 'condensed graphical view' simplifies the visual analysis of represented domain architectures. Integrated applications allow users to visualize and edit multiple alignments and build sequence divergence trees. Links to the relevant structural data in Protein Data Bank (PDB) and Homology derived Secondary Structure of Proteins (HSSP) are also provided.

Animals↗

PubMed2003

MAVID multiple alignment server.

MAVID is a multiple alignment program suitable for many large genomic regions. The MAVID web server allows biomedical researchers to quickly obtain multiple alignments for genomic sequences and to subsequently analyse the alignments for conserved regions. MAVID has been successfully used for the alignment of closely related species such as primates and also for the alignment of more distant organisms such as human and fugu. The server is fast, capable of aligning hundreds of kilobases in less than a minute. The multiple alignment is used to build a phylogenetic tree for the sequences, which is subsequently used as a basis for identifying conserved regions in the alignment. The server can be accessed at http://baboon.math.berkeley.edu/mavid/.

Animals↗

PubMed2004

Whole-genome analysis of Alu repeat elements reveals complex evolutionary history.

Alu repeats are the most abundant family of repeats in the human genome, with over 1 million copies comprising 10% of the genome. They have been implicated in human genetic disease and in the enrichment of gene-rich segmental duplications in the human genome, and they form a rich fossil record of primate and human history. Alu repeat elements are believed to have arisen from the replication of a small number of source elements, whose evolution over time gives rise to the 31 Alu subfamilies currently reported in Repbase Update. We apply a novel method to identify and statistically validate 213 Alu subfamilies. We build an evolutionary tree of these subfamilies and conclude that the history of Alu evolution is more complex than previous studies had indicated.

Alu Elements↗

PubMed2004

Mutations in the pale aleurone color1 regulatory gene of the Zea mays anthocyanin pathway have distinct phenotypes relative to the functionally similar TRANSPARENT TESTA GLABRA1 gene in Arabidopsis thaliana.

The pale aleurone color1 (pac1) locus, required for anthocyanin pigment in the aleurone and scutellum of the Zea mays (maize) seed, was cloned using Mutator transposon tagging. pac1 encodes a WD40 repeat protein closely related to anthocyanin regulatory proteins ANTHOCYANIN11 (AN11) (Petunia hybrida [petunia]) and TRANSPARENT TESTA GLABRA1 (TTG1) (Arabidopsis thaliana). Introduction of a 35S-Pac1 transgene into A. thaliana complemented multiple ttg1 mutant phenotypes, including ones nonexistent in Z. mays. Hybridization of Z. mays genomic BAC clones with the pac1 sequence identified an additional related gene, mp1. PAC1 and MP1 deduced protein sequences were used as queries to build a phylogenetic tree of homologous WD40 repeat proteins, revealing an ancestral gene duplication leading to two clades in plants, the PAC1 clade and the MP1 clade. Subsequent duplications within each clade have led to additional WD40 repeat proteins in particular species, with all mutants defective in anthocyanin expression contained in the PAC1 clade. Substantial differences in pac1, an11, and ttg1 mutant phenotypes suggest the evolutionary divergence of regulatory mechanisms for several traits that cannot be ascribed solely to divergence of the dicot and monocot protein sequences.

Alleles↗

PubMed2001

Genomic style of proteins: concepts, methods and analyses of ribosomal proteins from 16 microbial species.

We have introduced the concept of genomic 'style' of proteins. By style we understand those properties of a large set of proteins which are specific to the genome of one species (species primary-self) and different from the genome of another species (species contrasted-self). To characterise the style, we took advantage of the frequencies of amino acids and dipeptides present in non-identical segments of the complete set of orthologous ribosomal proteins encoded by 16 microbial species. We confirm the dependence of the overall amino acid composition on the genomic (G+C) content, and introduce a rectification procedure making it possible to extricate appropriate species-specific characteristics, which are no longer related to this content. The rectified frequencies are used to calculate inter-species distance matrices, and to build genomic evolutionary trees. Remarkably, the phylograms derived from the frequencies of non-identical residues in proteins closely resemble the classical phylograms based upon the conservation of identical residues in ribosomal RNAs. We believe that the concept of genomic style of proteins can be a useful tool for the study of evolution.

Amino Acid Sequence↗

PubMed2006

Eliminating child labour in Malawi: a British American Tobacco corporate responsibility project to sidestep tobacco labour exploitation.

OBJECTIVES: To examine British American Tobacco and other tobacco industry support of the Eliminating Child Labour in Tobacco Growing Foundation. DESIGN: Analyses of internal tobacco industry documents and ethnographic data. RESULTS: British American Tobacco co-founded the Eliminating Child Labour in Tobacco Growing Foundation (ECLT) in October 2000 and launched its pilot project in Malawi. ECLT's initial projects were budgeted at US2.3 million dollars over four years. Labour unions and leaf dealers, through ECLT funds, have undertook modest efforts such as building schools, planting trees, and constructing shallow wells to address the use of child labour in tobacco farming. In stark contrast, the tobacco companies receive nearly US40 million dollars over four years in economic benefit through the use of unpaid child labour in Malawi during the same time. BAT's efforts to combat child labour in Malawi through ECLT was developed to support the company's "corporate social responsibility agenda" rather than accepting responsibility for taking meaningful steps to eradicate child labour in the Malawi tobacco sector. CONCLUSION: In Malawi, transnational tobacco companies are using child labour projects to enhance corporate reputations and distract public attention from how they profit from low wages and cheap tobacco.

Agriculture↗

PubMed2001

The cephalic neural crest provides pericytes and smooth muscle cells to all blood vessels of the face and forebrain.

Most connective tissues in the head develop from neural crest cells (NCCs), an embryonic cell population present only in vertebrates. We show that NCC-derived pericytes and smooth muscle cells are distributed in a sharply circumscribed sector of the vasculature of the avian embryo. As NCCs detach from the neural folds that correspond to the future posterior diencephalon, mesencephalon and rhombencephalon, they migrate between the ectoderm and the neuroepithelium into the anterior/ventral head, encountering mesoderm-derived endothelial precursors. Together, these two cell populations build a vascular tree rooted at the departure of the aorta from the heart and ramified into the capillary plexi that irrigate the forebrain meninges, retinal choroids and all facial structures, before returning to the heart. NCCs ensheath each aortic arch-derived vessel, providing every component except the endothelial cells. Within the meninges, capillaries with pericytes of diencephalic and mesencephalic neural fold origin supply the forebrain, while capillaries with pericytes of mesodermal origin supply the rest of the central nervous system, in a mutually exclusive manner. The two types of head vasculature contact at a few defined points, including the anastomotic vessels of the circle of Willis, immediately ventral to the forebrain/midbrain boundary. Over the course of evolution, the vertebrate subphylum may have exploited the exceptionally broad range of developmental potentialities and the plasticity of NCCs in head remodelling that resulted in the growth of the forebrain.

Animals↗

PubMed2004

Target detection and recognition improvements by use of spatiotemporal fusion.

We developed spatiotemporal fusion techniques for improving target detection and automatic target recognition. We also investigated real IR (infrared) sensor clutter noise. The sensor noise was collected by an IR (256 x 256) sensor looking at various scenes (trees, grass, roads, buildings, etc.). More than 95% of the sensor pixels showed near-stationary sensor clutter noise that was uncorrelated between pixels as well as across time frames. However, in a few pixels (covering the grass near the road) the sensor noise showed nonstationary properties (with increasing or decreasing mean across time frames). The natural noise extracted from the IR sensor, as well as the computer-generated noise with Gaussian and Rayleigh distributions, was used to test and compare different spatiotemporal fusion strategies. Finally, we proposed two advanced detection schemes: the double-thresholding the reverse-thresholding techniques. These techniques may be applied to complicated clutter situations (e.g., very-high clutter or nonstationary clutter situations) where the traditional constant-false-alarm-ratio technique may fail.

Journal Article↗

PubMed2002

Acoustic detection of termite infestations in urban trees.

A portable, low-frequency acoustic system was used to detect termite infestations in urban trees. The likelihood of infestation was rated independently by a computer program and an experienced listener that distinguished insect sounds from background noises. Because soil is a good insulator, termite sounds could be detected easily underneath infested trees, despite the presence of high urban background noise. Termite sounds could be detected also in trunks, but background noise often made it difficult to identify termite signals unambiguously. High likelihoods of termite infestation were predicted at four live oak (Quercus virginiana Mill, Fagacae), two loblolly pine (Pinus taeda L., Pinacae), and two baldcypress (Taxodium distichum Rich. Pinacae) trees that wood-baited traps had identified as infested with Coptotermes formosanus Shiraki. Infestations also were predicted at two pine trees with confirmed recoveries of Reticulitermes flavipes (Kollar). Low likelihoods of infestation were predicted in four oak trees where no termites were found. Additional tests were conducted in anechoic environments to determine the range of acoustic detectability and the feasibility of acoustically estimating termite population levels. There was a significant regression between the activity rate and the number of termites present in a wood trap block, with a minimum detectable number of approximately 50 workers per liter of wood. The success of these field tests suggests that currently available acoustic systems have considerable potential to detect and monitor hidden infestations of termites in urban trees and around building perimeters in addition to their present uses to detect and monitor termite infestations in buildings.

Acoustics↗