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PubMed2003

Analysis of multiple single nucleotide polymorphisms of candidate genes related to coronary heart disease susceptibility by using support vector machines.

Coronary heart disease (CHD) is a complex genetic disease involving gene-environment interaction. Many association studies between single nucleotide polymorphisms (SNPs) of candidate genes and CHD have been reported. We have applied a new method to analyze such relationships using support vector machines (SVMs), which is one of the methods for artificial neuronal network. We assumed that common haplotype implicit in genotypes will differ between cases and controls, and that this will allow SVM-derived patterns to be classifiable according to subject genotypes. Fourteen SNPs of ten candidate genes in 86 CHD patients and 119 controls were investigated. Genotypes were transformed to a numerical vector by giving scores based on difference between the genotypes of each subject and the reference genotypes, which represent the healthy normal population. Overall classification accuracy by SVMs was 64.4% with a receiver operating characteristic (ROC) area of 0.639. By conventional analysis using the chi2 test, the association between CHD and the SNP of the scavenger receptor B1 gene was most significant in terms of allele frequencies in cases vs. controls (p = 0.0001). In conclusion, we suggest that the application of SVMs for association studies of SNPs in candidate genes shows considerable promise and that further work could be usefully performed upon the estimation of CHD susceptibility in individuals of high risk.

Alleles↗

PubMed1999

Distinct patterns of active and non-active plaques using texture analysis on brain NMR images in multiple sclerosis patients: preliminary results.

The benefits of texture analysis of magnetic resonance images have been assessed in multiple sclerosis (MS) patients. Out of thirty-two lesions identified in eight MS patients, nine were considered active, judging from their gadolinium uptake. Texture analysis allowed to obtain forty-two characterizing parameters for each lesion. Using discriminant analysis as a statistical method allowed to classify the lesions into two groups: active or non-active. An attempt to classify their level of activity by using only co-occurrence matrices was unsuccessful. Alternately, the same type of analysis performed on runlength analysis criteria allowed the accurate classification of 88% of active lesions and 96% of non-active lesions. Using incremental discriminate analysis can reduce the number of useful parameters. This method showed that among the 42 parameters, 8 only were highly significant and permitted an accurate classification. Five of these parameters are runlength parameters, and three others are more directly related to the global distribution. The main interest of runlength parameters is that they allowed to demonstrate that the lesion structure was different in active and non-active plaques. This preliminary work suggests that using texture analysis could be of interest in the follow-up of MS patients because it provides an opportunity to identify active lesions without frequent gadolinium injections.

Adult↗

PubMed2005

Incidence and risk factors for liver enzyme elevation during highly active antiretroviral therapy in HIV-HCV co-infected patients: results from the Italian EPOKA-MASTER Cohort.

BACKGROUND: The risk of hepatotoxicity associated with different highly active antiretroviral therapy (HAART) regimens (containing multiple-protease inhibitors, single-protease inhibitors or non nucleoside reverse transcriptase inhibitors) in HIV-HCV co-infected patients has not been fully assessed. METHODS: Retrospective analysis of a prospective cohort of 1,038 HIV-HCV co-infected patients who commenced a new HAART in the Italian MASTER database. Patients were stratified into naïve and experienced to antiretroviral therapy before starting the study regimens. Time to grade > or =III hepatotoxicity (as by ACTG classification) was the primary outcome. Secondary outcome was time to grade IV hepatotoxicity. RESULTS: Incidence of grade > or =III hepatotoxicity was 17.71 per 100 patient-years (p-yr) of follow up in naïve patient group and 8.22 per 100 p-yrs in experienced group (grade IV: 4.13 per 100 p-yrs and 1.08 per 100 p-yrs, respectively). In the latter group, the only independent factors associated with shorter time to the event at proportional hazards regression model were: previous liver transaminase elevations to grade > or =III, higher baseline alanine amino-transferase values, and use of a non nucleoside reverse transcriptase inhibitor based regimen. In the naive group, baseline aspartate transaminase level was associated with the primary outcome. CONCLUSION: Use of a single or multiple protease inhibitor based regimen was not associated with risk of hepatotoxicity in either naïve or experienced patient groups to a statistically significant extent. A cautious approach with strict monitoring should be applied in HIV-HCV co-infected experienced patients with previous liver transaminase elevations, higher baseline alanine amino-transferase values and who receive regimens containing non nucleoside reverse transcriptase inhibitors.

Adult↗

PubMed2002

Multiple comparisons model-based clustering and ternary pattern tree numerical display of gene response to treatment: procedure and application to the preclinical evaluation of chemopreventive agents.

Microarray technology has greatly aided the identification of genes that are expressed differentially. Statistical analysis of such data by multiple comparisons procedures has been slow to develop, in part, because methods to cluster the results of such comparisons in biologically meaningful ways have not been available. We isolated and analyzed, by Northern blot and GeneChip, replicate liver RNA samples (n = 4/group) from rats fed with control diet or diet containing one of three chemopreventive compounds, selected because their pharmacological activities, including RNA expression response, are relatively well understood. We report on a classification tree, based on the results of nonparametric multiple comparisons, which results in the bipolar hierarchical clustering of genes in relation to their response to treatment. In addition to identifying treatment-responsive genes, application of this procedure to our test study identified the known pharmacological relationships among the treatment groups without supervision. Also, small treatment-specific subsets of genes were identified that may be indicative of additional pharmacophores present in the test compounds.

Animals↗

PubMed1994

Quantitative modeling and biology: the multivariate approach.

Even though elegant examples of mathematical modeling of biological problems exist, such approaches still remain outside the domain of most biologists. It is proposed that, for a wider and more systematic use of mathematical models in biology, the soft modeling approaches, which are applicable to phenomena with a limited level of definition, should be investigated and preferred. In particular, multivariate data analysis (MDA) is indicated as an important tool toward fulfilling this goal. This paper reviews the general principles of MDA and examines in detail principal component analysis and cluster analysis, which are two of the most important MDA techniques. A number of applications to real biological problems are presented. These examples show how the construction of classifications corresponds to the generation of new knowledge and new concepts, which are hierarchically on a higher level than the initial information. This new form of knowledge is obtained without superimposing a priori theories on the data. It is demonstrated how the MDA can lead to the identification of biological systems; also shown is their ability to describe multiple scale phenomena, a typical feature of biological systems. Moreover, the multivariate analyses provide new descriptors for a given biological system; these descriptors are quantitative, thus allowing the system to be described in a "metric space," where it then becomes possible to use any other mathematical tool.

Animals↗

PubMed2002

Important amino acid properties for determining the transition state structures of two-state protein mutants.

Understanding the mechanism in the folding pathways of proteins is an important problem in molecular biology. The Phi-value analysis provides insight into the transition state structures during protein folding. In this work, we have analyzed the relationship between the observed Phi values upon mutations in two-state proteins (FK506 binding protein, chymotrypsin inhibitor and src SH3 domain) and the changes in 48 various physico-chemical, energetic and conformational properties. We found that the classification of mutations based on solvent accessibility improved the correlation significantly. The relationship between conformational properties and Phi values determines the presence/absence of secondary structures in the transition state. In buried mutations, the physical properties volume, shape and flexibility, and the thermodynamic properties enthalpy, entropy and free-energy change have significant correlation with Phi. The short and medium-range non-bonded energy in partially buried mutations and average long-range contacts in exposed mutations showed a strong correlation with Phi values. Multiple regression analysis incorporating combinations of three properties from among all possible combinations of the 48 properties increased the correlation coefficient up to 0.99, by an average rise of 20% for all the data sets. Information about local sequence and structure is more important in surface mutations than those in buried mutations for explaining the transition state structures of two-state proteins. Further, the implications of our results for understanding the process of protein folding have been discussed.

Amino Acid Sequence↗

PubMed1999

A quadratic discriminant analysis of protein structure classification based on the Helix/Strand content.

Based on the 210 non-homologous proteins (domains) classified manually by Michie et al. (J. Mol. Biol. 262, 168-185, 1996), a new structure classification criterion of globular proteins relying on the content of helix/strand has been proposed, using a quadratic discriminant method. Each protein is classified into one of the three classes, i.e. those of alpha class, beta class and alphabeta class (including alpha/beta and alpha+beta classes). According to the new structure classification criterion, of the 210 proteins in the training set, 207 are correctly classified and thus the accuracy is 207/210=98.57%. Multiple cross-validation tests are performed. The jackknife test shows that of the 210 proteins 207 are correctly classified with an accuracy of 98.57%. To test the method further, of 3577 proteins (domains) extracted from SCOP, 91.39% of them are correctly reclassified by the new classification criterion. On average, the accuracy of the new criterion is about 8 percentage points higher than that of the criterion proposed by Nakashima et al. (J. Biochem. 99, 153-162, 1986). Our result shows that the classification based solely on structures is basically consistent with that combining both structural and evolutionary information. Further complete automated classification scheme should consider both structures and evolutionary relationship. The methodology presented provides an appropriate mathematical format to reach this goal.

Animals↗

PubMed1985

[Multiple myeloma with 5-year survival. Study of initial prognostic factors. Role of beta-2-microglobulin].

A series of 21 patients with multiple myeloma and a survival of more than 5 years was compared to another series of 70 cases of myeloma, which all died within less than 5 years. The statistical analysis of these two groups revealed six factors with a significant prognostic value. The population with a long term survival presented: a low incidence of large tumour masses (stage III according to Durie and Salmon's classification): 24 per cent compared with 72 per cent p less than 0.01); a frequency on asymptomatic or minimally symptomatic forms of 29 per cent versus 7 per cent in the control series (p less than 0.001); a haemoglobin level of 7.3 mmol/l versus 6.4 mmol/l (p less than 0.01); a low beta-2-microglobulin level (4 mg/l versus 11 mg/l) (p less than 0.02); a usually normal serum creatinine level (p less than 0.05). Retrospectively, the authors also observed that the response to treatment constituted an essential prognostic factor (69 per cent response compared with 20 per cent) (p less than 0.001). The serum calcium, the immunological type, the level of monoclonal component and the marrow plasmocytosis did not differ between the two groups. The authors consider all of these parameters, together with the calcitonin hypocalcaemia test to be useful in three situations: the therapeutic decision in minimally symptomatic patients, the choice between single agent or combination chemotherapy, the establishment of criteria of remission and suspension of treatment.

Adult↗

PubMedDate not supplied

Type of statistical techniques in rheumatology and internal medicine journals.

A comparison of the prevalence and type of statistical analysis used in internal medicine and rheumatology journals was done. Four representative journals of each specialty were selected and twelve original articles were randomly obtained from each journal. The papers were reviewed twice within a three month interval by the same evaluator following published definitions for classification. The rheumatology journals tended to use fewer (80 versus 115) and simpler statistical techniques (X3 = 4.28, DF = 1, p = 0.03; OR, 95% CI = 3.21, 1.05-10.85). There was a statistical difference in the utilization of statistical procedures among journals in the four categories evaluated. Seven statistical techniques were required to have access to 86% of statistical tests used in rheumatology journals (t-tests, contingency tables, descriptive statistics, non-parametric comparisons, anova, multiple regression, and Pearson's correlation). The internal medicine journals required six statistical procedures to have access to 85% of the tests (contingency tables, survival analysis, epidemiologic statistics, t-tests, non-parametric statistics, and anova). Our results could be useful to plan medical education in biostatistics emphasizing the statistical techniques most commonly used in these areas.

Internal Medicine↗

PubMed1978

Restriction enzyme analysis of mitochondrial DNAs of petite mutants of yeast: classification of petites, and deletion mapping of mitochondrial genes.

We have analyzed the restriction digest patterns of the mitochondrial DNA from 41 cytoplasmic petite strains of Saccharomyces cerevisiae, that have been extensively characterized with respect to genetic markers. Each mitochondrial DNA was digested with seven restriction endonucleases (EcoRI, HPaI, HindIII, BamHI, HhaI, SalI, and PstI) which together make 41 cuts in grande mitochondrial DNA and for which we have derived fragment maps. The petite mitochondrial DNAs were also analyzed with HpaII, HaeIII, and AluI, each of which makes more than 80 cleavages in grande mitochondrial DNA. On the basis of the restriction patterns observed (i.e., only one fragment migrating differently from grande for a single deletion, and more than one for multiple deletions) and by comparing petite and grande mitochondrial DNA restriction maps, the petite clones could be classified into two main groups: (1) petites representing a single deletion of grande mitochondrial DNA and (2) petites containing multiple deletions of the grande mitochondrial DNA resulting in rearranged sequences. Single deletion petites may retain a large portion of the grande mitochondrial genome or may be of low kinetic cimplexity. Many petites which are scored as single continuous deletions by genetic criteria were later demonstrated to be internally deleted by restriction endonuclease analysis. Heterogeneous sequences, manifested by the presence of sub-stoichiometric amounts of some restriction fragments, may accompany the single or multiple deletions. Single deletions with heterogeneous sequences remain useful for mapping if the low concentration sequences represent a subset of the stoichiometric bands. Using a group of petites which retain single continuous regions of the grande mitochondrial DNA, we have physically mapped antibiotic resistance and mit- markers to regions of the grande restriction map as follows: C (99.3--1.4 map units)--OXI-1 (2.5--15.7)--OXI-2 (18.5--25)--P (28.1--34.2)--OXI-3 (32.2--61.2--OII (60--62)--COB (64.6--80.8--0I (80.4--85.7)--E (95--98.9).

DNA Restriction Enzymes↗

PubMed2005

[Early prediction of functional outcome one year after initial unilateral hemispheric stroke].

BACKGROUND AND PURPOSE: Several prognostic factors have been identified for outcome after stroke. We conducted a study to determine early predictive factors of functional outcome one year after stroke and to evaluate which factors are independent predictors, with an aim of specifying the role of age, aphasia, unilateral neglect, cognitive impairment and family social support. METHODS: Observational cohort study of 156 patients. All patients admitted to the university hospital for initial unilateral hemispheric stroke were included. The study duration was two years (inclusion, one year, and follow-up, one year) . The initial evaluation of stroke was conducted at day 2 and day 15 and included the Motricity Index and Trunk Control Test, New Functional Ambulation Classification, Frenchay arm test, Mini-Mental State Examination, Boston Diagnostic Aphasia Examination, unilateral neglect evaluation, and depression. Data on functional recovery (Barthel Index) were collected at day 360. RESULTS: The average age of patients was 72 years. Age was correlated to social situation (P<0.01) and previous neurological impairment (P<0.01). A multiple regression analysis, including 14 initial clinical factors correlated with the Barthel Index score at day 360, revealed 4 independent early predictive factors of outcome: initial score of Barthel Index at day 2 and its progression from day 2 to day 15, disorders of the executive functions and previous neurological impairment. CONCLUSION: In our cohort, in accordance with previous studies, age, cognitive impairment, unilateral neglect, aphasia, depression and social situation are not independent factors of poor outcome after stroke as evaluated by the Barthel Index.

Aged↗

PubMed1996

Retroviral aetiopathogenesis of ovine pulmonary carcinoma: a critical appraisal.

Although it has long been thought that a retrovirus is the responsible agent for ovine pulmonary carcinoma (OPC), identification of a replicative viral agent has proven difficult. Recently, the genome of a new retrovirus, jaagsiekte sheep retrovirus (JSRV), found in the lung-wash of affected sheep lung, has been cloned and sequenced; characterization of this virus and its consistent presence in tumor cells argue for its role as the aetiologic agent of OPC. Analysis of the nucleic acid sequence of the JSRV genome, suggests a new class of retrovirus, one that is chimeric according to the morphological classification scheme used for retroviruses. The genome of this virus does not appear to contain an oncogene, and the mechanism by which it causes disease is still unknown. The presence of multiple copies of endogenous retroviruses related to JSRV in DNA of OPC-affected and unaffected sheep further complicates investigation of oncogenesis in OPC. This review examines the evidence for a retrovirus as the causative agent for OPC, with particular emphasis on the viruses studied to date. The significance of endogenous JSRV-related sequences is considered. The mechanisms by which a retrovirus such as JSRV might induce lung tumours in sheep, and which of these are most likely, are discussed in light of these developments, as are the prospects for new means of diagnosis and treatment of this disease.

Animals↗

PubMed2002

Genomic approaches to the pathogenesis and treatment of acute lymphoblastic leukemias.

During the past 2 years, gene expression-profiling technology has been used to characterize multiple tumor types. These studies represent the initial attempts to understand cancer at the whole genome level and have given us our first glimpse into what can be learned from such analysis. This technology is beginning to be applied to the study of human leukemias. Recent studies focusing on lymphoblastic leukemia have provided insight into classification and pathogenesis.

Gene Expression Profiling↗

PubMed2004

Factors predicting progression of gastric intestinal metaplasia: results of a randomised trial on Helicobacter pylori eradication.

BACKGROUND AND AIMS: Gastric intestinal metaplasia (IM) is generally considered to be a precancerous lesion in the gastric carcinogenesis cascade. This study identified the risk factors associated with progression of IM in a randomised control study. SUBJECTS AND METHODS: A total of 587 Helicobacter pylori infected subjects were randomised to receive a one week course of anti-Helicobacter therapy (omeprazole, amoxicillin, and clarithromycin (OAC)) or placebo. Subjects underwent endoscopy with biopsy at baseline and at five years. Severity of IM was graded according to the updated Sydney classification and progression was defined as worsening of IM scores at five years in either the antrum or corpus, or development of neoplasia. Backward stepwise multiple logistic regression was used to identify independent risk factors associated with IM progression. RESULTS: Of 435 subjects (220 in the OAC and 215 in the placebo group) available for analysis, 10 developed gastric cancer and three had dysplasia. Overall progression of IM was noted in 52.9% of subjects. Univariate analysis showed that persistent H pylori infection, age >45 years, male subjects, alcohol use, and drinking water from a well were significantly associated with IM progression. Duodenal ulcer and OAC treatment were associated with a reduced risk of histological progression. Progression of IM was more frequent in those with more extensive and more severe IM at baseline. With multiple logistic regression, duodenal ulcer (odds ratio (OR) 0.23 (95% confidence interval (CI) 0.09-0.58)) was found to be an independent protective factor against IM progression. Conversely, persistent H pylori infection (OR 2.13 (95% CI 1.41-3.24)), age >45 years (OR 1.92 (95% CI 1.18-3.11)), alcohol use (OR 1.67 (95% CI 1.07-2.62)), and drinking water from a well (OR 1.74 (95% CI 1.13-2.67)) were independent risk factors associated with IM progression. CONCLUSION: Eradication of H pylori is protective against progression of premalignant gastric lesions.

Aged↗

PubMed1984

Hyperactive children: a study of the content analysis of their speech.

A group of hyperactive boys with attention deficit disorder (DSM-III) (n = 13) was compared to a group of normative, nonhyperactive boys (n = 16) with respect to Gottschalk-Gleser scores derived from 5-min speech samples they produced in response to standardized and purposely ambiguous instructions. The hyperactive boys had significantly higher mean scores than the normative boys for cognitive impairment, social alienation-personal disorganization, and total depression. Of the eight depression subscales, the hyperactive boys had significantly elevated scores on hopelessness, self-accusation (a cluster composed of shame, guilt, and hostility inwards), and psychomotor retardation. Problems with the classification of the hyperactive syndrome, which is equated with the attention deficit disorder, are briefly discussed. The present study gives some support to the concept, as adjudged from the content analysis of verbal behavior, that hyperactivity, at least in boys, may be associated with cognitive impairment, increased general psychiatric morbidity, and depression. Whether single or multiple etiological factors are involved in this disorder cannot be ascertained from this study.

Attention Deficit Disorder with Hyperactivity↗

PubMed1998

[An evaluation of the biting force, the body composition and the amount of masticatory action in young females].

UNLABELLED: The purposes of this study were to investigate factors related to maximum biting force and to understand the characteristics of physical properties of daily ingested foods in young females. One hundred and forty subjects aged 18-23, with Angle 1 class occlusion, had not suffered from periodontitis, and had not been treated for preparation of tooth crown of first molars. Body height and weight were measured, and percentage of body fat, fat mass (FM) and lean body mass (LBM) were estimated, using the impedance analyzer. The maximum biting force was measured by the press sensation method. According to the formula on the basis of our new version of Yanagisawa's food classification, the mean value of the amount of masticatory action for one day was calculated. Subjects were divided into the normal biting force and the low biting force groups with -1SD of the maximum biting force, in order to compare body composition and backgrounds in sports activities between these two groups. Multiple linear regression analysis was carried out, employing maximum biting force (kg.f) as a dependent variable, and having a background in sports activities, FM, LBM, the number of missing teeth, the number of dental caries and the amount of masticatory action for one day as independent variables. Results were as in the following: 1) The proportion of subjects who had a background in sports activities in the low biting force group were less than that in the normal biting force group (p < 0.01). 2) Having a background in sports activities and LBM were positively correlated to maximum biting force (p < 0.01), while the amount of masticatory action for one day was not. 3) All subjects, especially those in the low biting force group seldom had food requiring the highest amount of masticatory action. CONCLUSION: Having a background in sports activities and LBM are positively correlated with the maximum biting force, while the amount of masticatory action for one day was not correlated positively nor negatively in young females.

Adolescent↗

PubMed1994

[A multivariate prospective study of prognostic factors in non-small-cell lung carcinoma (NSCLC): the results at 5 years].

We present the results of a 5-year prospective study of 153 patients with a diagnosis of bronchogenic carcinoma (BC) who underwent curative surgery. Clinical and anatomical variables were analyzed by multiple regression analysis for prediction of death. Among the anatomical variables, the most significant were the following: stages of anatomical spread (p < or = 0.00000), ganglionic state (p < or = 0.00000), type for surgery (curative or non-curative) (p < or = 0.00000) and state of tumor (p = 0.00012). Significant clinical variables were clinical stage by Feinstein's classification (p = 0.00037), functional capacity (ECOG scale) (p = 0.01196) and tumor size measured conventionally (p = 0.01196). These variables were entered into a multivariate model for prognostic prediction in order to determine the patient's relative risk over time. The best combination of anatomical variables was obtained by associating the stages of spread and ganglionic state (chi 2 = 34.24; p = < 0.00000); the best combination of clinical variables was clinical stage and tumor size (chi 2 = 17.37; p = 0.00023). Thus, although the anatomical variables are more important than clinical ones, the latter have independent prognostic value, are easy to obtain and are available before surgery. They therefore represent an alternative to prognosis based on anatomical spread.

Adult↗

PubMed2000

Remission status defined by immunofixation vs. electrophoresis after autologous transplantation has a major impact on the outcome of multiple myeloma patients.

We have retrospectively analysed 344 multiple myeloma (MM) patients (202 de novo patients) treated in a non-uniform way in whom high-dose therapy and autologous stem cell transplantation (ASCT) response was simultaneously measured by both electrophoresis (EP) and immunofixation (IF). Patients in complete remission (CR) by EP were further subclassified as CR1 when IF was negative and CR2 when it remained positive. Partial responders (PR) were also subclassified as PR1 (very good PR, > 90% reduction in M-component) or PR2 (50-90% reduction). CR1 patients showed a significantly better event-free survival (EFS) [35% at 5 years, 95% confidence interval (CI) 17-53, median 46 months] and overall survival (OS) (72% at 5 years, CI 57-86, median not reached) compared with any other response group (univariate comparison P < 0.00000 to P = 0. 004). In contrast, comparison of CR2 with PR1 and with PR2 did not define different prognostic subgroups (median EFS 30, 30 and 26 months respectively, P = 0.6; median survival 56, 44 and 42 months respectively, P = 0.5). The non-responding patients had the worst outcome (5-year OS 8%, median 7 months). Multivariate analysis confirmed both the absence of differences among CR2, PR1 and PR2 and the highly discriminatory prognostic capacity of a three-category classification: (i) CR1 (ii) CR2 + PR1 + PR2, and (iii) non-response (EFS P < 0.00000; OS P < 0.00000; both Cox models P < 0.00000). In the logistic regression analysis, the factors significantly associated with failure to achieve CR1 were the use of two or more up-front chemotherapy lines, status of non-response pre-ASCT and inclusion of total body irradiation (TBI) in the preparative regimen. Tandem transplants or the use of multiple agents (busulphan and melphalan) in the preparative regimen resulted in a higher CR1 level; none of the biological factors explored influenced the possibility of achieving CR1. These results confirm that, in MM patients undergoing ASCT, achieving a negative IF identifies the patient subset with the best prognosis; accordingly, therapeutic strategies should be specifically designed to achieve negative IF.

Electrophoresis↗