PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Variant interpretation”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,045 records · Page 58Linked to original sources
PubMed1993

Electrophoretic analysis of protein-induced DNA bending and twist changes.

DNA fragments with a varied phasing of two intrinsic bends at their ends and a tet operator in-between were constructed to determine Tet repressor-induced twist changes in the operator DNA. These distance variants show a sinusoidal dependence of their electrophoretic mobilities on the phasing of their bends in polyacrylamide gels. Complex formation with Tet repressor leads to a displacement of the first minimum, indicating an unwinding of the tet operator DNA. Model calculations were performed to assess the contribution of Tet repressor-induced DNA bending to this result. They revealed that the amplitude of the electrophoretic mobilities of the distance variants may be used as a parameter to separate the effects of Tet repressor-induced twist change and bending. The systematic analysis presented here may help to improve the quantitative interpretation of gel shifts and promote the use of this highly sensitive method to gain structural information about protein-DNA complexes.

Antiporters↗
PubMed1990

The emergence of strategic knowledge activation in categorical clustering during retrieval.

Elementary school children's free recall clustering has recently been explained as an automatic by-product of their developing knowledge base. In contrast, it is claimed that as children get older they become aware of the usefulness of category organization as a memory strategy that enables them to strategically activate category knowledge even during retrieval. To test this hypothesis an experimental procedure was developed where Ss first had to learn items in a noncategorical order to the criterion of two perfect serial recall trials. After a 12- to 15-min retention interval Ss unexpectedly received either serial or free recall (or--in Experiment 1--cued recall) instructions. In three experiments with second and fourth graders it was shown that (1) fourth graders' recall exceeded that of second graders only in the free, but not in the serial (or cued), recall condition, (2) higher levels of clustering were observed for fourth graders in the free recall condition, and (3) the grade effect on free recall data was eliminated when the influence of metamemory and categorical clustering statistically was partialled out (Experiments 1 and 3). This pattern of results proved robust against variants in which a metamemory question was asked or omitted prior to recall (Experiment 2) and manipulations in which age differences in categorical knowledge were minimized (Experiment 3). The results were interpreted as demonstrating fourth graders' strategic competence in activating category knowledge during retrieval and second graders' automatic knowledge activation.

Attention↗
PubMed2006

Myxoglobulosis of the appendix associated with a proximal carcinoid and a pseudodiverticulum.

A 37-year-old woman presented with acute right lower abdominal pain. Intraoperatively, the appendix was enlarged and distended. The lumen of the appendix was tightly filled with pearl-like globules, diagnostic of myxoglobulosis, a rare variant of mucocele of the appendix. A carcinoid of 2.0 cm diameter was found in the proximal region of the appendix. The appendiceal mucosa showed hyperplastic-adenomatous changes. A pseudodiverticulum interpreted as evidence of increased intraluminal pressure was detected. The latter may be an adjunct to the proximal partial obstruction of the appendiceal lumen by the carcinoid in the development of the spheroids of myxoglobulosis.

Adult↗
PubMed2006

Genetic associations in preterm birth: a primer of marker selection, study design, and data analysis.

Spontaneous preterm birth (PTB; delivery before 37 weeks gestation) is a primary risk factor for infant morbidity and mortality. The etiology is unclear, but there is evidence that there is a genetic predisposition to PTB. Armed with the suggestion of genetic risk factors and the failure to identify useful biomarkers, investigators are starting to actively pursue the role of genetic predisposition in PTB. Several studies have been done to date assessing the role of single gene variants. However, positive findings have failed to replicate. We argue that heterogeneity in study designs, definition of phenotype, single-nucleotide polymorphism (SNP) selection, population selection, and sample size makes data interpretation difficult in complex phenotypes such as PTB. In this review, we introduce general concepts of study designs in genetic epidemiology, selection of candidate genes and markers for analysis, and analytical methodologies. We also introduce how the concept of gene-gene interactions (biologic epistasis) and gene-environment interactions may affect the predisposition to PTB.

Female↗
PubMed2006

Clustering of autoimmune diseases in families with a high-risk for multiple sclerosis: a descriptive study.

BACKGROUND: Autoimmune mechanisms are thought to have a major role in the pathogenesis of multiple sclerosis. We aimed to identify coexisting autoimmune phenotypes in patients with multiple sclerosis from families with several members with the disease and in their first-degree relatives. METHODS: A total of 176 families (386 individuals and 1107 first-degree relatives) were characterised for a history of other autoimmune disorders. Family-based or case-control analyses were done to assess the association of cytotoxic T-lymphocyte-antigen 4 (CTLA4) and protein tyrosine phosphatase (PTPN22) variants with susceptibility to multiple sclerosis. FINDINGS: 46 (26%) index cases reported at least one coexisting autoimmune disorder. The most common were Hashimoto thyroiditis (10%), psoriasis (6%), inflammatory bowel disease (3%), and rheumatoid arthritis (2%). 112 (64%) families with a history of multiple sclerosis reported autoimmune disorders (excluding multiple sclerosis) in one or more first-degree relatives, whereas 64 (36%) families reported no history of autoimmunity. Similar to index cases, Hashimoto thyroiditis, psoriasis, and inflammatory bowel disease were also the most common disorders occurring in family members. A common variant within CTLA4 was strongly associated with multiple sclerosis in families who had other autoimmune diseases (p=0.009) but not in families without a history of other autoimmune disorders (p=0.90). INTERPRETATION: The presence of various immune disorders in families with several members with multiple sclerosis suggests that the disease might arise on a background of a generalised susceptibility to autoimmunity. This distinct multiple-sclerosis phenotype, defined by its association with other autoimmune diseases, segregates with specific genotypes that could underlie the common susceptibility.

Alleles↗
PubMed2003

Geno2pheno: Estimating phenotypic drug resistance from HIV-1 genotypes.

Therapeutic success of anti-HIV therapies is limited by the development of drug resistant viruses. These genetic variants display complex mutational patterns in their pol gene, which codes for protease and reverse transcriptase, the molecular targets of current antiretroviral therapy. Genotypic resistance testing depends on the ability to interpret such sequence data, whereas phenotypic resistance testing directly measures relative in vitro susceptibility to a drug. From a set of 650 matched genotype-phenotype pairs we construct regression models for the prediction of phenotypic drug resistance from genotypes. Since the range of resistance factors varies considerably between different drugs, two scoring functions are derived from different sets of predicted phenotypes. Firstly, we compare predicted values to those of samples derived from 178 treatment-naive patients and report the relative deviance. Secondly, estimation of the probability density of 2000 predicted phenotypes gives rise to an intrinsic definition of a susceptible and a resistant subpopulation. Thus, for a predicted phenotype, we calculate the probability of membership in the resistant subpopulation. Both scores provide standardized measures of resistance that can be calculated from the genotype and are comparable between drugs. The geno2pheno system makes these genotype interpretations available via the Internet (http://www.genafor.org/).

Anti-HIV Agents↗
PubMed1996

Second-site reversion of a structural defect in bacteriophage T4 lysozyme.

A plasmid-borne gene encoding bacteriophage T4 lysozyme with a structural mutation, Tyr161-Ala, was mutagenized by by the use of polymerase chain reaction. The mutagenized gene was inserted into a specialized bacteriophage lambda cloning vector that must acquire a functional lysozyme gene in order to form plaques. Functional variants of the mutant lysozyme were selected. Three compensatory second-site revertants were obtained: Thr152-Met, Lys43-Ile, and Thr151-Ala. The effects of these mutations are interpreted in light of previous structural and genetic studies of T4 lysozyme.

Bacteriophage T4↗
PubMed2003

Structure-based phenotyping predicts HIV-1 protease inhibitor resistance.

Mutations in HIV-1 drug targets lead to resistance and consequent therapeutic failure of antiretroviral drugs. Phenotypic resistance assays are time-consuming and costly, and genotypic rules-based interpretations may fail to predict the effects of multiple mutations. We have developed a computational procedure that rapidly evaluates changes in the binding energy of inhibitors to mutant HIV-1 PR variants. Models of WT complexes were produced from crystal structures. Mutant complexes were built by amino acid substitutions in the WT complexes with subsequent energy minimization of the ligand and PR binding site residues. Accuracy of the models was confirmed by comparison with available crystal structures and by prediction of known resistance-related mutations. PR variants from clinical isolates were modeled in complex with six FDA-approved PIs, and changes in the binding energy (DeltaE(bind)) of mutant versus WT complexes were correlated with the ratios of phenotypic 50% inhibitory concentration (IC(50)) values. The calculated DeltaE(bind) of five PIs showed significant correlations (R(2) = 0.7-0.8) with IC(50) ratios from the Virco Antivirogram assay, and the DeltaE(bind) of six PIs showed good correlation (R(2) = 0.76-0.85) with IC(50) ratios from the Virologic PhenoSense assay. DeltaE(bind) cutoffs corresponding to a four-fold increase in IC(50) were used to define the structure-based phenotype as susceptible, resistant, or equivocal. Blind predictions for 78 PR variants gave overall agreement of 92% (kappa = 0.756) and 86% (kappa = 0.666) with PhenoSense and Antivirogram phenotypes, respectively. The structural phenotyping predicted drug resistance of clinical HIV-1 PR variants with an accuracy approaching that of frequently used cell-based phenotypic assays.

Algorithms↗
PubMed1999

Homozygotes for prothrombin gene 20210 A allele in a thrombophilic family without clinical manifestations of venous thromboembolism.

BACKGROUND AND OBJECTIVE: A new genetic risk factor for venous thromboembolism has recently been described which involves a G to A transition at position 20210 in the 3' untranslated region of the prothrombin gene. To date, only a few homozygotes for this mutation have been reported and in most of cases, they suffered from thrombotic disease. Here, we describe a pedigree including both heterozygous and homozygous subjects for prothrombin (PT) 20210 A. DESIGN AND METHODS: This family was recruited in 1996 as part of our GAIT (Genetic Analysis of Idiopathic Thrombophilia) project. To qualify for the GAIT study, a pedigree was required to have at least 10 living individuals in three or more generations (i.e. extended pedigree). The pedigrees were selected through probands with idiopathic thrombophilia. A complete set of plasma and DNA determinations related to hemostasis was performed on this family. RESULTS: The plasma studies yielded normal results in all of the individuals. The family members who had a history of thromboembolism were heterozygous carriers of the PT 20210 A variant. In addition, 4 relatives who were heterozygous, and two who were homozygous for this A allele, failed to show clinical manifestations. These two homozygotes were 51 and 19 years old. INTERPRETATION AND CONCLUSIONS: This case exemplifies the complexity of thrombotic disease since individuals homozygous for a mutant gene do not exhibit symptoms while heterozygous individuals often do exhibit the disease. This case suggests that the new genetic risk factor for thrombosis (i.e. PT 20210 A) may not be as strong as most of the previously described genetic risk factors.

3' Untranslated Regions↗
PubMed1988

[An introduction to iatrogenic pathology].

The authors presented the current conception of iatrogenesis in wide interpretation consistent with The International Classification of the Diseases and Causes of Death (the IX revision). The tendencies in iatrogenesis determination are analysed. Soviet and foreign literature data published on iatrogenic variants, frequency rate, problems for pathologists, classification, medical-pathological and social aspects are delineated.

Diagnosis↗
PubMed1994

Ensuring the consistency of rDNA-derived biologicals: the contribution of gene sequencing.

The past few years have seen an interesting debate on the extent to which DNA-sequencing of expression systems is appropriate as a basis for assessing the quality and consistency of rDNA-derived products. While there is a need to improve and validate the ability of end-product testing procedures to detect low levels of variant proteins, there are several reasons why it may not be justified to require extensive DNA sequence analysis of large numbers of individual clones of producer cells. These include difficulties in interpreting the resultant data due to artefacts introduced by PCR and the fact that other events, such as translational errors and chemical and enzymic alterations during production and downstream processing, also lead to potential heterogeneity of pharmaceutical proteins. The evaluation of these products can only be made at the protein level. Some DNA sequencing will be required during product development, but in practice the quality and consistency of rDNA-derived products are best determined by a range of in-process and end-product testing procedures, including the use of biological assays and standardization.

Biological Products↗
PubMed1989

Caffeine toxicity is inversely related to DNA repair in simian virus 40-transformed xeroderma pigmentosum cells irradiated with ultraviolet light.

Human cells transformed by simian virus 40 (SV40) are more sensitive to killing by ultraviolet light when grown in caffeine after irradiation. The degree of sensitization at 2 mM caffeine (expressed as the ratio of the 37% survival dose for control cells divided by the 37% survival dose for cells grown in caffeine, i.e., the dose modification factor) was approximately 1.9 in transformed normal cells and 3.8-5.8 in excision-defective xeroderma pigmentosum (XP) groups A, C, and D cells. A large dose modification factor of 12 was observed in a transformed XP variant cell line. Chinese hamster ovary cells were not significantly different from transformed normal human cells, with a maximum dose modification factor of 1.5. Two radioresistant XP revertants that do not excise cyclobutane dimers gave different responses; one resembled its group A parent in being sensitized by caffeine, and one did not. These results can be interpreted on the basis of a single hypothesis that cells are killed as a result of attempts to replicate damaged DNA. Increased replication rates caused by transformation, increased numbers of replication forks in DNA caused by caffeine, and increased numbers of damaged sites ahead of replication forks in excision-defective cells are all processes that will consequently increase killing according to this hypothesis. A corollary is that the XP variant may be highly sensitized to caffeine because of excision defects at the DNA replication forks, an idea that may be important in designing cloning strategies for the XP variant gene.

Animals↗
PubMed2001

New mutations in exon 28 of the von Willebrand factor gene detected in patients with different types of von Willebrand's disease.

BACKGROUND AND OBJECTIVES: von Willebrand's disease (vWD), the most common hereditary bleeding disorder in humans, is caused by qualitative and/or quantitative deficiencies of von Willebrand factor, and can manifest itself under several different phenotypes. Most of the molecular defects have been detected in qualitative variants involving exon 28 of the vWF gene. Patients from four unrelated families with different types of vWD were included in the mutation screening of this region. DESIGN AND METHODS: The whole exon 28 was analyzed in three gene specific fragments, two of them comprising the region involved in the platelet glycoprotein Ib vWF interaction. The search for mutations was carried out by single-stranded conformation polymorphism analysis. The mutations were then identified by automatic sequencing of the anomalous electrophoretic pattern samples. RESULTS: The following candidate mutations were detected. The 3941T-->A transversion, which predicts the amino acid change V1314D, was detected in a sporadic patient with type 2B vWD and severe thrombocytopenia. The 4309G-->A transition, resulting in the amino acid substitution A1437T, was identified in four patients classified as having type 2M vWD. Six unclassified patients from another family carry the 4135C-->T mutation, which gives rise to a cysteine instead of the normal arginine (R1379C) that segregates with the phenotype. The amino acid change C1227R, predicted by the mutation 4135C-->T, was identified as a compound heterozygote in a patient with moderately severe type 1 vWD. None of these mutations had been described previously. INTERPRETATION AND CONCLUSIONS: These findings confirm the importance already given to this region for the correct function of von Willebrand factor since the mutations detected, which affect the D3 and A1 domains, could give rise to different variants of the disease.

Child↗
PubMed2004

Genomic biomarkers for cancer assessment: implementation challenges for laboratory practice.

Genomic biomarkers are an emerging class of laboratory tests, which present special implementation challenges for clinical laboratory services, compared to conventional laboratory tests. These challenges, which include analytical, bioinformatics, bioethical, interpretation and commercialization issues, represent real obstacles to widespread implementation of these tests. Technical challenges include the capacity to detect and identify many different kinds of markers for different diseases in a short time period, capacity to identify simultaneously gene rearrangements, amplification, inhibition, deletions and replications. Bioinformatics challenges include rapid analysis of genomic data, as well as the cross reference to other genomic data, and to other laboratory tests. Bioethical issues relate to consent to retain and use genetic data, which may be obtained inadvertently during analysis for genomic markers. Interpretation challenges include observations that the particular genomic markers may not be independent variables, as other undetected genomic alterations could invalidate or alter genomic marker interpretation. Further, as early experience with predictive genetic markers for cancer has shown, proprietary commercial interests may conflict with public health values of identifying genomic markers in subject populations. Based on our 10 years of experience with genomic biomarkers, important implementation strategies for genomic markers include development of:Standard high throughput analyzers capable of detecting any alteration of any genomic variant at any time. Bioinformatics analysis online, coupled to stored patient data. Laboratory service framework that preserves confidentiality but integrates genomic data with other laboratory tests. Laboratory service framework, which links consents, genomic analysis, reports to both specimen and data repositories. Overall, the laboratory service challenges for genomic markers are to manage very large analytical sets and very large data sets in finite time with responsible interpretation, all within finite funding. To meet these challenges, implementation strategies beyond the one disease, one diagnosis, one genomic marker concept must begin now.

Biomarkers, Tumor↗
PubMed2005

Recognizing partially occluded, expression variant faces from single training image per person with SOM and soft kappa-NN ensemble.

Most classical template-based frontal face recognition techniques assume that multiple images per person are available for training, while in many real-world applications only one training image per person is available and the test images may be partially occluded or may vary in expressions. This paper addresses those problems by extending a previous local probabilistic approach presented by Martinez, using the self-organizing map (SOM) instead of a mixture of Gaussians to learn the subspace that represented each individual. Based on the localization of the training images, two strategies of learning the SOM topological space are proposed, namely to train a single SOM map for all the samples and to train a separate SOM map for each class, respectively. A soft kappa nearest neighbor (soft kappa-NN) ensemble method, which can effectively exploit the outputs of the SOM topological space, is also proposed to identify the unlabeled subjects. Experiments show that the proposed method exhibits high robust performance against the partial occlusions and variant expressions.

Algorithms↗
PubMed2005

Analysis of discrepancies in the interpretation of antiretroviral drug resistance results in HIV-1 infected patients of Basque Country, Spain.

BACKGROUND: Genotypic and phenotypic analysis of HIV-1 resistance mutations constitute one important point for providing guidelines in the choice of antiretroviral regimens and to design lines of rescue treatment for patients holding HIV-1 drug-resistant variants. However, some levels of discordance among them has been described. OBJECTIVES: (i) To compare the genotypic analysis of resistance mutations to reverse transcriptase (RT) and protease (PR) inhibitors by Stanford HIVdb program (http://hivdb.stanford.edu) (St-HIVdb), and genotype with quantitative phenotypic analysis (Virtual Phenotype, VircoNET). (ii) To identify drug resistance mutations associated with discrepant results. STUDY DESIGN: Five hundred HIV-1 infected patients were included in this study. RNA was extracted from plasma. RT and PR regions were amplified and sequenced using ABI-Prism DNA sequencing system. Sequences were corrected and assembled with Seqman and Bioedit computer programs. The corrected sequences were submitted to the Stanford HIV-Seq program (http://hivdb.stanford.edu) and to Virtual Phenotype (VircoNET). RESULTS: Discrepant cases were considered if results were high or intermediate resistant by Stanford HIV-Seq program and susceptible by Virtual Phenotype, being detected as follows: (i) nucleoside RT inhibitors (NRT): 31.7% (ABC), 31% (d4T), 29.5% (ddC), 27.6% (ddI), 14.3% (TDF) and 11.3% (ZDV) and to PR inhibitors: 8.8% (SQV), 5% (APV), 3.8% (NFV) and 3.2% (IDV). These discrepant results were related to the presence of thymidine analogue mutations (TAMs) and also to key resistance mutations to NRT inhibitors: 65R, 69D/N, 74V/I, 184V/I and 215Y/F. (ii) PR inhibitors: 82A/F/T/S, 84I and 90M. Concordant results were considered when the interpretations by both programs were coincident, being higher than 96.7% for non-NRT inhibitors. CONCLUSIONS: The detection of discrepant results to NRT inhibitors and PR inhibitors, including the analysis of sequences with key resistant mutations to some drugs, means that further investigation is necessary in order to establish which is the best interpretation system as antiretroviral therapy guide.

Algorithms↗
PubMed1996

Assessment of tumor cell cohesion in vivo using pattern interpretation by cellular automata.

OBJECTIVE: There is abundant evidence that patterning in life sciences may be closely related to the functional properties of the constitutive elements. In order to estimate some of these functional properties by examining the static pattern evolved, pattern interpretation by cellular automata (PICA) was introduced and applied to the mechanisms of tumor growth. Previously it was shown that the estimates concerning tumor cell proliferation and motility were consistent with those obtained by other methods. STUDY DESIGN: Morphologic patterns obtained by growing two variants of the C4 cervical carcinoma cell lines with different in vitro adhesive properties in the hamster cheek pouch were evaluated by PICA. RESULTS: PICA estimates of tumor cell cohesion turned out to be significantly higher in tumors derived from the C4-I cell line (0.73 +/- 0.02 SD) with high in vitro cohesiveness than in tumors derived from the less adhesive C4-II cell line (0.32 +/- 0.04 SD; t test, P = .001). CONCLUSION: These results indicate that functional estimates concerning tumor cell cohesion obtained by PICA may be in good agreement with in vitro observations of the same cellular property and further underscore that PICA may be a useful tool for the functional interpretation of static histologic patterns.

Animals↗