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PubMed2005

Grid requirements for the integration of biomedical information resources for health applications.

OBJECTIVES: The goal of this paper is to identify how Grid technology can be applied for the development and deployment of integration systems, bringing together distributed and heterogeneous biomedical information sources for medical applications. METHODS: The integration of new genetic and medical knowledge in clinical workflows requires the development of new paradigms for information management in which the ability to access and relate disparate data sources is essential. We adopt a requirements perspective based on the user needs we have identified in the development of the INFOGENMED system to assess current Grid technology against those requirements. RESULTS: The gap between Grid features and distributed biomedical information integration needs is characterized. Results from prospective studies are also reported. CONCLUSIONS: Grid infrastructures offer advanced features for the deployment of collaborative computational environments across virtual organizations. New Grid developments are in line with the problem of multiple site information integration. From the INFOGENMED point of view, Grid infrastructures need to evolve to implement structured data access services and semantic content description and discovery.

Computational Biology↗
PubMed2005

Application of a rank-based genetic association test to age-at-onset data from the Collaborative Study on the Genetics of Alcoholism study.

Association studies of quantitative traits have often relied on methods in which a normal distribution of the trait is assumed. However, quantitative phenotypes from complex human diseases are often censored, highly skewed, or contaminated with outlying values. We recently developed a rank-based association method that takes into account censoring and makes no distributional assumptions about the trait. In this study, we applied our new method to age-at-onset data on ALDX1 and ALDX2. Both traits are highly skewed (skewness > 1.9) and often censored. We performed a whole genome association study of age at onset of the ALDX1 trait using Illumina single-nucleotide polymorphisms. Only slightly more than 5% of markers were significant. However, we identified two regions on chromosomes 14 and 15, which each have at least four significant markers clustering together. These two regions may harbor genes that regulate age at onset of ALDX1 and ALDX2. Future fine mapping of these two regions with densely spaced markers is warranted.

Adult↗
PubMed2003

Canine Imerslund-Gräsbeck syndrome maps to a region orthologous to HSA14q.

Selective malabsorption of cobalamin (vitamin B(12)) accompanied by proteinuria, known as Imerslund-Gräsbeck syndrome or megaloblastic anemia 1 (I-GS, MGA1; OMIM 261100), is a rare autosomal recessive disorder. In Finnish kindreds, I-GS is caused by mutations in the cubilin gene ( CUBN), located on human Chromosome (Chr) 10. However, not all patients have CUBN mutations, and three distinct mutations in the amnionless gene, AMN, were very recently identified in patients from Norwegian and Israeli families. The present study demonstrates that in a large canine I-GS pedigree, the disease is genetically linked (peak multipoint LOD score 11.74) to a region on dog Chr 8 that exhibits conserved synteny with human Chr 14q. Multipoint analysis indicates that the canine disease gene lies in an interval between the echinoderm microtubule-associated, protein-like 1 ( EML1) gene and the telomere. A single critical recombinant further suggests that the disease gene is between markers in EML1 and the G protein-coupled receptor ( G2A) gene, defining an I-GS interval in the human genome that contains the AMN gene. Thus, these comparative-mapping data provide evidence that canine I-GS is a homologue of one form of the human disease and will provide a useful system for understanding the molecular mechanisms underlying the disease in humans.

Anemia, Megaloblastic↗
PubMed2004

In silico study of transcriptome genetic variation in outbred populations.

Dissecting the genetic architecture of regulatory elements on a genome-wide basis is now technically feasible. The potential medical and genetical implications of this kind of experiment being very large, it is paramount to assess the reliability and repeatability of the results. This is especially relevant in outbred populations, such as humans, where the genetic architecture is necessarily more complex than in crosses between inbred lines. Here we simulated a chromosome-wide SNP association study using real human microarray data. Our model predicted, as observed, a highly significant clustering of quantitative trait loci (QTL) for gene expression. Importantly, the estimates of QTL positions were often unstable, and a decrease in the number of individuals of 16% resulted in a loss of power of approximately 30% and a large shift in the position estimate in approximately 30-40% of the remaining significant QTL. We also found that the analysis of two repeated measures of the same mRNA can also result in two QTL that are located far apart. The intrinsic difficulties of analyzing outbred populations should not be underestimated. We anticipate that (many) conflicting results may be collected in the future if whole-genome association studies for mRNA levels are carried out in outbred populations.

Alleles↗
PubMed2006

Distinguishable haplotype blocks in the HTR3A and HTR3B region in the Japanese reveal evidence of association of HTR3B with female major depression.

BACKGROUND: Genetic variations in the serotonin receptor 3A (HTR3A) and 3B (HTR3B) genes, positioned in tandem on chromosome 11q23.2, have been shown to be associated with psychiatric disorders in samples of European ancestry. But the polymorphisms highlighted in these reports map to different locations in the two genes, therefore it is unclear which gene exerts a stronger effect on susceptibility. METHODS: To determine the haplotype block structure in the genomic regions of HTR3A and HTR3B, and to examine whether genetic variations in the region show evidence of association with schizophrenia and affective disorder in the Japanese, we performed haplotype-based case-control analysis using 29 polymorphisms. RESULTS: Two haplotype blocks each were revealed for HTR3A and HTR3B in Japanese samples. In HTR3B, haplotype block 2 that included a nonsynonymous single nucleotide polymorphism (SNP), yielded evidence of association with major depression in females (global p = .0023). Analysis employing genome-wide SNPs using the STRUCTURE program did not detect population stratification in the samples. CONCLUSIONS: Our results suggest an important role for HTR3B in major depression in women and also raise the possibility that previously proposed disease-associated SNPs in the HTR3A/B region in Caucasians are in linkage disequilibrium with haplotype block 2 of HTR3B in the Japanese.

Adult↗
PubMed2004

Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2.

Many sequence variants in predisposition genes are of uncertain clinical significance, and classification of these variants into high- or low-risk categories is an important problem in clinical genetics. Classification of such variants can be performed by direct epidemiological observations, including cosegregation with disease in families and degree of family history of the disease, or by indirect measures, including amino acid conservation, severity of amino acid change, and evidence from functional assays. In this study, we have developed an approach to the synthesis of such evidence in a multifactorial likelihood-ratio model. We applied this model to the analysis of three unclassified variants in BRCA1 and three in BRCA2. The evidence strongly suggests that two variants (C1787S in BRCA1 and D2723H in BRCA2) are deleterious, three (R841W in BRCA1 and Y42C and P655R in BRCA2) are neutral, and one (R1699Q in BRCA1) remains of uncertain significance. These results provide a demonstration of the utility of the model.

Base Sequence↗
PubMed2006

Cultured lymphocytes from autistic children and non-autistic siblings up-regulate heat shock protein RNA in response to thimerosal challenge.

There are reports suggesting that some autistic children are unable to mount an adequate response following exposure to environmental toxins. This potential deficit, coupled with the similarity in clinical presentations of autism and some heavy metal toxicities, has led to the suggestion that heavy metal poisoning might play a role in the etiology of autism in uniquely susceptible individuals. Thimerosal, an anti-microbial preservative previously added routinely to childhood multi-dose vaccines, is composed of 49.6% ethyl mercury. Based on the levels of this toxin that children receive through routine immunization schedules in the first years of life, it has been postulated that thimerosal may be a potential triggering mechanism contributing to autism in susceptible individuals. One potential risk factor in these individuals may be an inability to adequately up-regulate metallothionein (MT) biosynthesis in response to presentation of a heavy metal challenge. To investigate this hypothesis, cultured lymphocytes (obtained from the Autism Genetic Resource Exchange, AGRE) from autistic children and non-autistic siblings were challenged with either 10 microM ethyl mercury, 150 microM zinc, or fresh media (control). Following the challenge, total RNA was extracted and used to query "whole genome" DNA microarrays. Cultured lymphocytes challenged with zinc responded with an impressive up-regulation of MT transcripts (at least nine different MTs were over-expressed) while cells challenged with thimerosal responded by up-regulating numerous heat shock protein transcripts, but not MTs. Although there were no apparent differences between autistic and non-autistic sibling responses in this very small sampling group, the differences in expression profiles between those cells treated with zinc versus thimerosal were dramatic. Determining cellular response, at the level of gene expression, has important implications for the understanding and treatment of conditions that result from exposure to neurotoxic compounds.

Anti-Infective Agents, Local↗
PubMed2006

Do we need a uniform regulatory system for biobanks across Europe?

Within Europe, there is currently no uniform regulatory system that applies to human biobanks used for genetic research purposes. This has resulted in considerable variation in the national law that applies to the use of DNA samples, personal information and medical records in the countries across Europe. This could result in a situation where researchers collaborating across Europe may be operating unlawfully if they share research data and samples across borders where different laws are in operation. There are also concerns that the lack of standardised guidelines inhibits cooperation among researchers across Europe but also restricts the sharing of DNA samples and information across national borders, which is problematic for multinational companies and institutions carrying out collaborative research. Ultimately, the lack of a uniform regulatory system may have implications for the viability and long-term competitiveness of collaborative European research. The purpose of this paper is to discuss some of the preliminary issues that would need to be considered before such a regulatory system for biobanks could be developed within Europe.

Biological Specimen Banks↗
PubMed2005

Covariate linkage analysis of GAW14 simulated data incorporating subclinical phenotype, sex, population, parent-of-origin, and interaction.

BACKGROUND: We evaluate a method for the incorporation of covariates into linkage analysis using the Genetic Analysis Workshop 14 simulated data. Focusing on a randomly chosen replicate (42) we investigated the effect of the 12 subclinical phenotypes, sex, population, and parent-of-origin on the linkage signal from a model-free linkage analysis of Kofendrerd Personality Disorder. RESULTS: We detected a linkage peak on chromosome 1, at about 175 cM, which varied depending upon individuals' status for subclinical phenotype b. A linkage peak on chromosome 3 (310 cM) was found not to depend upon subclinical phenotype status. Further peaks were found on chromosomes 5 (12 cM), 9 (4 cM), and 10 (95 cM), depending on the status of subclinical phenotypes a, k, and c/d/g, respectively. CONCLUSION: Retrospective comparison of our results with the simulation model showed correct identification of disease loci D1-5 on chromosomes 1, 3, 5, 9 and 10, respectively.

Chromosome Mapping↗
PubMed2004

Versatile gene-specific sequence tags for Arabidopsis functional genomics: transcript profiling and reverse genetics applications.

Microarray transcript profiling and RNA interference are two new technologies crucial for large-scale gene function studies in multicellular eukaryotes. Both rely on sequence-specific hybridization between complementary nucleic acid strands, inciting us to create a collection of gene-specific sequence tags (GSTs) representing at least 21,500 Arabidopsis genes and which are compatible with both approaches. The GSTs were carefully selected to ensure that each of them shared no significant similarity with any other region in the Arabidopsis genome. They were synthesized by PCR amplification from genomic DNA. Spotted microarrays fabricated from the GSTs show good dynamic range, specificity, and sensitivity in transcript profiling experiments. The GSTs have also been transferred to bacterial plasmid vectors via recombinational cloning protocols. These cloned GSTs constitute the ideal starting point for a variety of functional approaches, including reverse genetics. We have subcloned GSTs on a large scale into vectors designed for gene silencing in plant cells. We show that in planta expression of GST hairpin RNA results in the expected phenotypes in silenced Arabidopsis lines. These versatile GST resources provide novel and powerful tools for functional genomics.

Arabidopsis↗
PubMed2001

A gene expression screen in zebrafish embryogenesis.

A screen for developmentally regulated genes was conducted in the zebrafish, a system offering substantial advantages for the study of the molecular genetics of vertebrate embryogenesis. Clones from a normalized cDNA library from early somitogenesis stages were picked randomly and tested by high-throughput in situ hybridization for restricted expression in at least one of four stages of development. Among 2765 clones that were screened, a total of 347 genes with patterns judged to be restricted were selected. These clones were subjected to partial sequence analysis, allowing recognition of functional motifs in 163 among them. In addition, a portion of the clones were mapped with the aid of the LN54 radiation hybrid panel. The usefulness of the in situ hybridization screening approach is illustrated by describing several new markers for the characteristic structure in the fish embryo named the yolk syncytial layer, and for different regions of the developing brain.

Animals↗
PubMed2004

Machine learning based pattern recognition applied to microarray data.

MOTIVATION: Microarrays have allowed the expression level of thousands of genes or proteins to be measured simultaneously. Data sets generated by these arrays consist of a small number of observations (e.g., 20-100 samples) on a very large number of variables (e.g., 10,000 genes or proteins). The observations in these data sets often have other attributes associated with them such as a class label denoting the pathology of the subject. Finding the genes or proteins that are correlated to these attributes is often a difficult task since most of the variables do not contain information about the pathology and as such can mask the identity of the relevant features. We describe a genetic algorithm (GA) that employs both supervised and unsupervised learning to mine gene expression and proteomic data. The pattern recognition GA selects features that increase clustering, while simultaneously searching for features that optimize the separation of the classes in a plot of the two or three largest principal components of the data. Because the largest principal components capture the bulk of the variance in the data, the features chosen by the GA contain information primarily about differences between classes in the data set. The principal component analysis routine embedded in the fitness function of the GA acts as an information filter, significantly reducing the size of the search space since it restricts the search to feature sets whose principal component plots show clustering on the basis of class. The algorithm integrates aspects of artificial intelligence and evolutionary computations to yield a smart one pass procedure for feature selection, clustering, classification, and prediction.

Algorithms↗
PubMed2006

Computation of recurrent minimal genomic alterations from array-CGH data.

MOTIVATION: The identification of recurrent genomic alterations can provide insight into the initiation and progression of genetic diseases, such as cancer. Array-CGH can identify chromosomal regions that have been gained or lost, with a resolution of approximately 1 mb, for the cutting-edge techniques. The extraction of discrete profiles from raw array-CGH data has been studied extensively, but subsequent steps in the analysis require flexible, efficient algorithms, particularly if the number of available profiles exceeds a few tens or the number of array probes exceeds a few thousands. RESULTS: We propose two algorithms for computing minimal and minimal constrained regions of gain and loss from discretized CGH profiles. The second of these algorithms can handle additional constraints describing relevant regions of copy number change. We have validated these algorithms on two public array-CGH datasets. AVAILABILITY: From the authors, upon request. CONTACT: celine@lri.fr SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Algorithms↗
PubMed2006

The S. purpuratus genome: a comparative perspective.

The predicted gene models derived from the sea urchin genome were compared to the gene catalogs derived from other completed genomes. The models were categorized by their best match to conserved protein domains. Identification of potential orthologs and assignment of sea urchin gene models to groups of homologous genes was accomplished by BLAST alignment and through the use of a clustering algorithm. For the first time, an overview of the sea urchin genetic toolkit emerges and by extension a more precise view of the features shared among the gene catalogs that characterize the super-clades of animals: metazoans, bilaterians, chordate and non-chordate deuterostomes, ecdysozoan and lophotrochozoan protostomes. About one third of the 40 most prevalent domains in the sea urchin gene models are not as abundant in the other genomes and thus constitute expansions that are specific at least to sea urchins if not to all echinoderms. A number of homologous groups of genes previously restricted to vertebrates have sea urchin representatives thus expanding the deuterostome complement. Obversely, the absence of representatives in the sea urchin confirms a number of chordate specific inventions. The specific complement of genes in the sea urchin genome results largely from minor expansions and contractions of existing families already found in the common metazoan "toolkit" of genes. However, several striking expansions shed light on how the sea urchin lives and develops.

Animals↗
PubMed2005

Gene expression microarray studies in polygenic psychiatric disorders: applications and data analysis.

Gene expression microarrays have become a mainstream technology that can provide valuable insight into psychiatric disorders. Gene expression studies in post mortem brain samples of schizophrenia and bipolar disorder have the potential to yield novel clues about the pathophysiology of these complex trait disorders. In the present review, a short introduction of the genetic and molecular background of schizophrenia and bipolar disorder is followed by a discussion of the basic concept and limits of gene expression microarray technology, and the complexities surrounding the analysis of thousands of gene transcripts. Although this review is intended for use in most platforms, it has a particular focus on the commercially available Affymetrix system. Various computer programs and their principal features are discussed, and it is shown how these programs can be applied to reveal a biological context of microarray findings. I will demonstrate how the programs can help to judge the results rather than focus on their statistical principles. The strength of gene array experiments is their emphasis on broad, biological themes, rather than on specific genes, and proper biostatistical approaches are important to ensure reproducibility of the findings. All results should be verified by independent means. This review is intended to help brain researchers who want to apply gene expression microarray technology to conceptualize research strategies and sample analysis.

Biomedical Research↗
PubMedDate not supplied

A multi-investigator/institutional DNA bank for AIDS-related human genetic studies: AACTG Protocol A5128.

BACKGROUND: An understanding of the relationships among allelic variability and clinical outcomes will be critical if HIV-infected patients are to benefit from the explosion in knowledge in human genomics. Human DNA banks must allow future analyses while addressing confidentiality, ethical, and regulatory issues. METHOD: A multidisciplinary group of clinical investigators, ethicists, data managers, regulatory specialists, and community representatives developed Adult AIDS Clinical Trials Group (AACTG) Protocol A5128. Participants in past or present AACTG clinical trials may contribute DNA. Extraction from whole blood is performed at a central laboratory, where participants' unique identifiers are replaced by randomly assigned identifiers prior to DNA storage. To identify genotype-phenotype relationships, genetic assay results can be temporarily linked to clinical trials data. RESULTS: Institutional review boards in 21 states and Puerto Rico have approved Protocol A5128, and accrual is ongoing. Of the first 4,247 enrollees, 82% are male, 56% are white, 26% are African American, and 15% are Hispanic. Because participants may participate in multiple AACTG protocols, these represent 11,424 cases in 324 different AACTG studies and substudies, with at least 100 participants from 24 different studies. Studies exploring specific genotype-phenotype relationships are underway. CONCLUSION: The AACTG DNA bank will be an important resource for genomic discovery relevant to HIV therapy.

Acquired Immunodeficiency Syndrome↗
PubMed2006

A biobank management model applicable to biomedical research.

BACKGROUND: The work of Research Ethics Boards (REBs), especially when involving genetics research and biobanks, has become more challenging with the growth of biotechnology and biomedical research. Some REBs have even rejected research projects where the use of a biobank with coded samples was an integral part of the study, the greatest fear being the lack of participant protection and uncontrolled use of biological samples or related genetic data. The risks of discrimination and stigmatization are a recurrent issue. In light of the increasing interest in biomedical research and the resulting benefits to the health of participants, it is imperative that practical solutions be found to the problems associated with the management of biobanks: namely, protecting the integrity of the research participants, as well as guaranteeing the security and confidentiality of the participant's information. METHODS: We aimed to devise a practical and efficient model for the management of biobanks in biomedical research where a medical archivist plays the pivotal role as a data-protection officer. The model had to reduce the burden placed on REBs responsible for the evaluation of genetics projects and, at the same time, maximize the protection of research participants. RESULTS: The proposed model includes the following: 1) a means of protecting the information in biobanks, 2) offers ways to provide follow-up information requested about the participants, 3) protects the participant's confidentiality and 4) adequately deals with the ethical issues at stake in biobanking. CONCLUSION: Until a governmental governance body is established in Quebec to guarantee the protection of research participants and establish harmonized guidelines for the management of biobanks in medical research, it is definitely up to REBs to find solutions that the present lack of guidelines poses. The model presented in this article offers a practical solution on a day-to-day basis for REBs, as well as researchers by promoting an archivist to a pivotal role in the process. It assures protection of all participants who altruistically donate their samples to generate and improve knowledge for better diagnosis and medical treatment.

Biological Specimen Banks↗
PubMed2006

JLIN: a java based linkage disequilibrium plotter.

BACKGROUND: A great deal of effort and expense are being expended internationally in attempts to detect genetic polymorphisms contributing to susceptibility to complex human disease. Techniques such as Linkage Disequilibrium mapping are being increasingly used to examine and compare markers across increasingly large datasets. Visualisation techniques are becoming essential to analyse the ever-growing volume of data and results available with any given analysis. RESULTS: JLIN (Java LINkage disequilibrium plotter) is a software package designed for customisable, intuitive visualisation of Linkage Disequilibrium (LD) across all common computing platforms. Customisation allows the user to choose particular visualisations, statistical measures and measurement ranges. JLIN also allows the user to export images of the LD visualisation in several common document formats. CONCLUSION: JLIN allows the user to visually compare and contrast the results of a range of statistical measures on the input dataset(s). These measures include the commonly used D' and r2 statistics and empirical p-values. JLIN has a number of unique and novel features that improve on existing LD visualisation tools.

Algorithms↗