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Biomedical subjects

Eivind Hovig

Publications and source records attributed to Eivind Hovig.

18 recordsLinked to original sources
PubMed2026

Family genetic designs in MoBa provide insights into health and functioning.

Genome-wide association studies using large, population-based samples of unrelated individuals have discovered thousands of genetic associations with health and disease1. These studies can help explain genetic and environmental risks. However, increasing evidence suggests that population-based estimates, while precise, can also reflect confounding that affects their use and interpretation. This confounding can be overcome using data from genotyped family members, such as nuclear mother-father-child trios2,3. However, samples of genotyped families are rare4-11. Here we illustrate some of the advantages of familial data using the Norwegian Mother, Father and Child Cohort Study (MoBa), a population-based cohort of parents and offspring with extensive genotype data (n ≈ 230,000) (ref. 3), along with broad and longitudinal phenotyping of health and functioning. We provide an overview of MoBa and describe the quality control of genotype data tailored to this extensively related sample. We then use trio data to illustrate how family-based genomic designs can identify distinct direct and indirect sources of genetic influence and structural confounding. As examples, we analyse children's height, educational achievement, depressive symptoms and sleep duration. These demonstrations highlight MoBa as a broadly valuable resource for advancing understanding of health and functioning across the lifecourse and generations.

Journal Article↗
PubMed2005

Response of malignant B lymphocytes to ionizing radiation: gene expression and genotype.

The human malignant B-lymphocyte cell lines Reh and U698 show arrest in G2 phase after ionizing radiation (IR), but only Reh cells arrest in G1 phase and die by apoptosis. We have used cDNA microarrays to measure changes in gene expression at 2, 4 and 6 hr after irradiation of Reh and U698 cells with 0.5 and 4 Gy in order to begin exploring the molecular mechanisms underlying the phenotypic changes. We also investigated whether gene expression changes could be caused by possible aberrations of genes, as measured by comparative genomic hybridization. Reh cells showed upregulation of CDKN1A that likely mediated the G1 arrest. In contrast, U698 cells have impaired function of TP53 protein and no activation of CDKN1A, suppressing the arrest in G1. The G2 arrest in both cell lines was likely due to repression of PLK1 and/or CCNF. IR-induced apoptosis in Reh cells was probably mediated by TP53 and CDKN1A, whereas a high expression level of MCL1, caused by gene amplification, and activation of the NFKB pathway may have suppressed the apoptotic response in U698 cells. Genes suggested to be involved in apoptosis were activated long before this phenotype was detectable and showed the same temporal expression profiles as genes involved in cell cycle arrest. Our results suggest that differences in functionality and/or copy number of several genes involved in IR-regulated pathways contributed to the phenotypic differences between Reh and U698 cells after IR, and that multiple molecular factors control the radiation response of malignant B lymphocytes.

Chromosome Aberrations↗
PubMed2004

Determination of hereditary mutations in the BRCA1 gene using archived serum samples and capillary electrophoresis.

Analysis of DNA variation in biological samples most frequently utilizes the polymerase chain reaction (PCR) performed on extracted genomic DNA, followed by visualization of alleles using various methodologies. Few reports have demonstrated that amplification of DNA from plasma and serum samples is possible. We have performed DNA amplification on a large set of serum samples (n = 2955). Here, we report that known hereditary mutations in the BRCA gene can efficiently be analyzed in serum samples collected and stored over several decades. Fragments were PCR-amplified following a short initial denaturation of the serum sample in a standard microwave oven. Fragment analysis was subsequently performed using a DNA capillary-sequencing instrument. The PCR success rates were fragment- and size-dependent ranging from 83.2% to 97.9%. Of the 11,820 polymerase chain reactions performed, the overall PCR success rate was 91.3% (10,796/11,820), which is comparable to PCR performed on genomic DNA. The advantage of the method described herein is its ability to utilize archival material stored in serum biobanks for long periods of time.

Base Sequence↗
PubMed2004

FigSearch: a figure legend indexing and classification system.

UNLABELLED: FigSearch is a prototype text-mining and classification system for figures from any corpus of full-text biological papers. The system allows users to search for figures that contain genes of interest and illustrate protein interactions. The retrieved figures are ranked by a score representing the likelihood to be of a certain type, in this case, schematic illustrations of protein interactions and signaling events. The system contains a Web interface for search, a module for classification of figures based on vector representations of figure legends and a module for indexing gene names. In a preliminary validation, the FigSearch system showed satisfactory performance according to domain experts in providing the most relevant graphical representations. This strategy may be easily extended to other figure types. Moreover, as more full-text data become available, such a system will find increased usefulness in identifying and presenting compressed biological knowledge. AVAILABILITY: A searchable Web interface, FigSearch, is accessible via http://pubgeneserver.uio.no/figsearch/ for all figures from the available corpus.

Abstracting and Indexing↗
PubMed2004

Profound influence of microarray scanner characteristics on gene expression ratios: analysis and procedure for correction.

BACKGROUND: High throughput gene expression data from spotted cDNA microarrays are collected by scanning the signal intensities of the corresponding spots by dedicated fluorescence scanners. The major scanner settings for increasing the spot intensities are the laser power and the voltage of the photomultiplier tube (PMT). It is required that the expression ratios are independent of these settings. We have investigated the relationships between PMT voltage, spot intensities, and expression ratios for different scanners, in order to define an optimal scanning procedure. RESULTS: All scanners showed a limited intensity range from 200 to 50 000 (mean spot intensity), for which the expression ratios were independent of PMT voltage. This usable intensity range was considerably less than the maximum detection range of the PMTs. The use of spot and background intensities outside this range led to errors in the ratios. The errors at high intensities were caused by saturation of pixel intensities within the spots. An algorithm was developed to correct the intensities of these spots, and, hence, extend the upper limit of the usable intensity range. CONCLUSIONS: It is suggested that the PMT voltage should be increased to avoid intensities of the weakest spots below the usable range, allowing the brightest spots to reach the level of saturation. Subsequently, a second set of images should be acquired with a lower PMT setting such that no pixels are in saturation. Reliable data for spots with saturation in the first set of images can easily be extracted from the second set of images by the use of our algorithm. This procedure would lead to an increase in the accuracy of the data and in the number of data points achieved in each experiment compared to traditional procedures.

Algorithms↗
PubMed2004

Real-time nucleic acid sequence-based amplification in nanoliter volumes.

Real-time nucleic acid sequence-based amplification (NASBA) is an isothermal method specifically designed for amplification of RNA. Fluorescent molecular beacon probes enable real-time monitoring of the amplification process. Successful identification, utilizing the real-time NASBA technology, was performed on a microchip with oligonucleotides at a concentration of 1.0 and 0.1 microM, in 10- and 50-nL reaction chambers, respectively. The microchip was developed in a silicon-glass structure. An instrument providing thermal control and an optical detection system was built for amplification readout. Experimental results demonstrate distinct amplification processes. Miniaturized real-time NASBA in microchips makes high-throughput diagnostics of bacteria, viruses, and cancer markers possible, at reduced cost and without contamination.

Humans↗
PubMed2004

Analysis of the humoral immune response to immunoselected phage-displayed peptides by a microarray-based method.

We describe a novel approach for high-throughput analysis of the immune response in cancer patients using phage-based microarray technology. The recombinant phages used for fabricating phage arrays were initially selected via the use of random peptide phage libraries and breast cancer patient serum antibodies. The peptides displayed by the phages retained their ability to be recognized by serum antibodies after immobilization. The recombinant phage microarrays were screened against either breast cancer or healthy donor serum antibodies. A model-based statistical method is proposed to estimate significant differences in serum antibody reactivity between patients and normals. A significant tumor effect was found with most of the selected phage-displayed peptides, suggesting that recombinant phage microarrays can serve as a tool in monitoring humoral responses towards phage-displayed peptides.

Amino Acid Sequence↗
PubMed2004

Constitutive expression of the AP-1 transcription factors c-jun, junD, junB, and c-fos and the marginal zone B-cell transcription factor Notch2 in splenic marginal zone lymphoma.

Splenic marginal zone lymphoma (SMZL) is a lymphoma type of putative marginal zone B-cell origin. No specific genetic alterations have yet been demonstrated in SMZL. Clinically, SMZL is a low-grade B-cell non-Hodgkin lymphoma. However, the presence of p53 mutation, 7q22-7q32 deletion or the absence of somatic hypermutations of immunoglobulin genes has been correlated with a worse prognosis. In this study, we analyzed genome-wide gene expression of 24 cases of SMZL using the microarray technique. The AP-1 transcription factors c-jun, junD, junB, and c-fos as well as Notch2 were found to be specifically up-regulated. These data were confirmed by real-time PCR and immunohistochemical staining of tissue sections. The absence of concordant high expression of the MAP kinases, the signaling cascade leading to AP-1 up-regulation, suggests autoregulation of the AP-1 transcription factors and an important role in SMZL oncogenesis. High expression of Notch2, a transcription factor that induces marginal zone B-cell differentiation, is highly suggestive for a marginal zone B-cell origin of SMZL. In addition, SMZL with the 7q deletion showed high expression of TGF-beta1 and low expression of the DNA helicase XPB, a crucial part of the nucleotide excision repair complex, possibly explaining the more aggressive clinical course of those cases.

Alleles↗
PubMed2003

Tumor classification and marker gene prediction by feature selection and fuzzy c-means clustering using microarray data.

BACKGROUND: Using DNA microarrays, we have developed two novel models for tumor classification and target gene prediction. First, gene expression profiles are summarized by optimally selected Self-Organizing Maps (SOMs), followed by tumor sample classification by Fuzzy C-means clustering. Then, the prediction of marker genes is accomplished by either manual feature selection (visualizing the weighted/mean SOM component plane) or automatic feature selection (by pair-wise Fisher's linear discriminant). RESULTS: The proposed models were tested on four published datasets: (1) Leukemia (2) Colon cancer (3) Brain tumors and (4) NCI cancer cell lines. The models gave class prediction with markedly reduced error rates compared to other class prediction approaches, and the importance of feature selection on microarray data analysis was also emphasized. CONCLUSIONS: Our models identify marker genes with predictive potential, often better than other available methods in the literature. The models are potentially useful for medical diagnostics and may reveal some insights into cancer classification. Additionally, we illustrated two limitations in tumor classification from microarray data related to the biology underlying the data, in terms of (1) the class size of data, and (2) the internal structure of classes. These limitations are not specific for the classification models used.

Biomarkers, Tumor↗
PubMed2003

MGraph: graphical models for microarray data analysis.

UNLABELLED: This paper introduces a MATLAB toolbox, MGraph, which applies graphical models as a natural environment to formulate and solve problems in microarray data analysis. MGraph with its graphical interface allows the user to predict genetic regulatory networks by a graphical gaussian model (GGM), and to quantify the effects of different experimental treatment conditions on gene expression profiles by a graphical log-linear model (GLM). The power of graphical models was explored and illustrated through two example applications. First, four MAPK pathways in yeast were meaningfully reconstructed through GGM. Second, GLM was used to quantify the contributions of sex, genotype and age to transcriptional variance in Drosophila melanogaster. This application may provide a valuable aid in the prediction of genetic regulatory networks, as well as in investigations of various experimental conditions that affect global gene expression profiles. AVAILABILITY: The MATLAB program MGraph is freely available at http://www.uio.no/~junbaiw/mgraph/mgraph.html for academics.

Algorithms↗
PubMed2003

Effects of mRNA amplification on gene expression ratios in cDNA experiments estimated by analysis of variance.

BACKGROUND: A limiting factor of cDNA microarray technology is the need for a substantial amount of RNA per labeling reaction. Thus, 20-200 micro-grams total RNA or 0.5-2 micro-grams poly (A) RNA is typically required for monitoring gene expression. In addition, gene expression profiles from large, heterogeneous cell populations provide complex patterns from which biological data for the target cells may be difficult to extract. In this study, we chose to investigate a widely used mRNA amplification protocol that allows gene expression studies to be performed on samples with limited starting material. We present a quantitative study of the variation and noise present in our data set obtained from experiments with either amplified or non-amplified material. RESULTS: Using analysis of variance (ANOVA) and multiple hypothesis testing, we estimated the impact of amplification on the preservation of gene expression ratios. Both methods showed that the gene expression ratios were not completely preserved between amplified and non-amplified material. We also compared the expression ratios between the two cell lines for the amplified material with expression ratios between the two cell lines for the non-amplified material for each gene. With the aid of multiple t-testing with a false discovery rate of 5%, we found that 10% of the genes investigated showed significantly different expression ratios. CONCLUSION: Although the ratios were not fully preserved, amplification may prove to be extremely useful with respect to characterizing low expressing genes.

Analysis of Variance↗
PubMed2003

Speed-up of DNA melting algorithm with complete nearest neighbor properties.

We describe an optimized algorithm, which is faster and more accurate compared to previously described algorithms, for computing the statistical mechanics of denaturation of nucleic acid sequences according to the classical Poland-Scheraga type of model. Nearest neighbor thermodynamics has been included in a complete and general way, by rigorously treating nearest neighbor interactions, helix end interactions, and isolated base-pairs. This avoids the simplifications of previous approaches and achieves full generality and controllability with respect to thermodynamic modeling. The algorithm computes subchain partition functions by recursion, from which various quantitative aspects of the melting process are easily derived, for example the base-pairing probability profiles. The algorithm represents an optimization with respect to algorithmic complexity of the partition function algorithm of Yeramian et al. (Biopolymers 1990, 30, 481-497): we reduce the computation time for a base-pairing probability profile from O(N2) to O(N), where N is the sequence length. This speed-up comes in addition to the speed-up due to a multiexponential approximation of the loop entropy factor as introduced by Fixman and Freire22 and applied by Yeramian et al. The speed-up, however, is independent of the multiexponential approximation and reduces time from O(N3) to O(N2) in the exact case. A method for representing very large numbers is described, which avoids numerical overflow in the partition functions for genomic length sequences. In addition to calculating the standard base-pairing probability profiles, we propose to use the algorithm to calculate various other probabilities (loops, helices, tails) for a more direct view of the melting regions and their positions and sizes. This can provide a better understanding of the physics of denaturation and the biology of genomes.

Algorithms↗
PubMed2003

S100A4 regulates membrane induced activation of matrix metalloproteinase-2 in osteosarcoma cells.

To study the role of the metastasis associated protein S100A4, an osteosarcoma cell line (OHS) with a high level of this protein was transfected with a vector containing a ribozyme that degrades S100A4 mRNA and, as controls, OHS cells were transfected with the vector alone. We have followed up our previous investigation (Bjørnland et al. 1999) by a detailed investigation of these cell lines' synthesis of MMP and TIMP proteins at different cell densities. It is shown that the cell lines with a low S100A4 level produced a reduced amount of immunoreactive MMP-2 at cellular subconfluence, while at confluence there was no difference compared to the control cells. The cell lines with a reduced S100A4 level produced less of the activated form of MMP-2 (62-kDa) and less TIMP-1 than the corresponding control cells, independent of cell density. Isolated cell membranes from cell lines with a reduced S100A4 level contained less MT1-MMP, MMP-2 and TIMP-2 compared to the control cells. Activation of exogenously added proMMP-2 was less effective with the former membrane preparations. It appeared that the mechanism behind the S100A4 dependent activation of proMMP-2 varied with cell density, as SN50, a peptide inhibitor of NF-kappaB nuclear translocation reduced the activation of MMP-2 at low cell density, but had no effect at high cell density. Thus, one of the mechanisms by which S100A4 may exert its effect on metastasis of some tumors is by regulating the MMP-2 activity.

Bone Neoplasms↗
PubMed2002

Analysis of repeatability in spotted cDNA microarrays.

We report a strategy for analysis of data quality in cDNA microarrays based on the repeatability of repeatedly spotted clones. We describe how repeatability can be used to control data quality by developing adaptive filtering criteria for microarray data containing clones spotted in multiple spots. We have applied the method on five publicly available cDNA microarray data sets and one previously unpublished data set from our own laboratory. The results demonstrate the feasibility of the approach as a foundation for data filtering, and indicate a high degree of variation in data quality, both across the data sets and between arrays within data sets.

Oligonucleotide Array Sequence Analysis↗
PubMed2002

Differential display analysis of breast carcinoma cells enriched by immunomagnetic target cell selection: gene expression profiles in bone marrow target cells.

The red bone marrow (BM) is an important indicator organ of hematogenous micrometastatic spread of carcinomas. Characterization of biological properties specific for BM micrometastatic cells, however, is technically challenging due to the limited number of target cells usually available for the purpose. This report provides referrals to qualitative gene expression profiling of BM micrometastatic cells enriched by immunomagnetic selection. First, an experimental strategy was used to study regulatory mechanisms involved when BM micrometastatic cells colonize distant organs. The MA-11 cells, originating from BM micrometastases in a breast cancer patient clinically devoid of overt metastatic disease, were injected into immunodeficient rats. Metastatic MA-11 cells were subsequently immunoselected from the resulting in vivo lesions. The selected cell populations were compared to the injected cells by differential display analysis, and several genes possibly involved in tumor cell invasion and proliferation were confirmed as differentially expressed among the various MA-11 cell populations. A direct approach to qualitative gene expression profiling of BM micrometastatic cells was also explored. Carcinoma cells were immunoselected from BM and axillary lymph nodes obtained from breast cancer patients, and the isolated cell populations were compared by differential display analysis. Two candidate genes, identified as factors involved in cellular growth control, appeared as differentially expressed by the target cells from BM. Our study provides detailed information on how to combine an immunomagnetic selection procedure and differential display analysis to reveal gene expression profiles that may characterize BM micrometastatic cells.

Animals↗
PubMed2002

MArray: analysing single, replicated or reversed microarray experiments.

UNLABELLED: MArray is a Matlab toolbox with a graphical user interface that allows the user to analyse single or paired microarray datasets by direct input of the raw data output file from image analysis packages, such as QuantArray or GenePiX. The application provides simple procedures to manually evaluate the quality of each measurement, multiple approaches to both ratio normalization (simple normalization, intensity dependent normalization) and evaluation of the reproducibility of paired experiments (using the techniques 'simple statistical method' and 'quality control ellipse' and 'significance analysis of microarrays'). Specifically, interactive spot evaluation functions are available in MArray and an online gene information database (NCBI UniGene) is linked. The application may provide a valuable aid in selecting and optimizing experimental procedures, as well as serving as an analytical tool for two-state biological comparisons, such as a study of single-dose activation. It is entirely platform independent, and only requires Matlab installed. AVAILABILITY: http://matrise.uio.no/marray/marray.html

Computer Graphics↗