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Murali Ramanathan

Publications and source records attributed to Murali Ramanathan.

At least 19 recordsLinked to original sources

A novel functional module detection algorithm for protein-protein interaction networks.

BACKGROUND: The sparse connectivity of protein-protein interaction data sets makes identification of functional modules challenging. The purpose of this study is to critically evaluate a novel clustering technique for clustering and detecting functional modules in protein-protein interaction networks, termed STM. RESULTS: STM selects representative proteins for each cluster and iteratively refines clusters based on a combination of the signal transduced and graph topology. STM is found to be effective at detecting clusters with a diverse range of interaction structures that are significant on measures of biological relevance. The STM approach is compared to six competing approaches including the maximum clique, quasi-clique, minimum cut, betweeness cut and Markov Clustering (MCL) algorithms. The clusters obtained by each technique are compared for enrichment of biological function. STM generates larger clusters and the clusters identified have p-values that are approximately 125-fold better than the other methods on biological function. An important strength of STM is that the percentage of proteins that are discarded to create clusters is much lower than the other approaches. CONCLUSION: STM outperforms competing approaches and is capable of effectively detecting both densely and sparsely connected, biologically relevant functional modules with fewer discards.

Journal Article↗

Pharmacogenetics of MXA SNPs in interferon-beta treated multiple sclerosis patients.

The myxovirus resistance A (MXA) mRNA has been extensively investigated for assessing the biologic responses of multiple sclerosis (MS) patients to interferon-beta (IFN-beta) therapy. The objective of this study was to evaluate the associations between two MXA promoter region single nucleotide polymorphisms (rs2071430 and rs17000900) and the gene expression responses, clinical and MRI phenotypes in IFN-beta treated MS patients. The rs2071430 and rs17000900 SNPs, which are located in or near an interferon-stimulated response element (ISRE), were genotyped in 179 relapsing MS patients. Quantitative MRI measurements were available for 101 patients on IFN-beta monotherapy. Gene expression was assessed in 22 anti-interferon-beta neutralizing antibody negative patients. No significant association was found between the MXA genotype at these two SNPs and clinical, MRI and MXA gene expression in MS patients treated with IFN-beta therapy.

Adult↗

Information-theoretic identification of predictive SNPs and supervised visualization of genome-wide association studies.

The size, dimensionality and the limited range of the data values makes visualization of single nucleotide polymorphism (SNP) datasets challenging. The purpose of this study is to evaluate the usefulness of 3D VizStruct, a novel multi-dimensional data visualization technique for SNP datasets capable of identifying informative SNPs in genome-wide association studies. VizStruct is an interactive visualization technique that reduces multi-dimensional data to three dimensions using a combination of the discrete Fourier transform and the Kullback-Leibler divergence. The performance of 3D VizStruct was challenged with several diverse, biologically relevant published datasets including the human lipoprotein lipase (LPL) gene locus, the human Y-chromosome in several populations and a multi-locus genotype dataset of coral samples from four populations. In every case, the SNPs and or polymorphic markers identified by the 3D VizStruct mapping were predictive of the underlying biology.

Animals↗

Dynamics of interferon-beta modulated mRNA biomarkers in multiple sclerosis patients with anti-interferon-beta neutralizing antibodies.

The objective of this study was to evaluate multiple interferon (IFN) specific mRNA biomarkers in multiple sclerosis (MS) patients with anti-IFN-beta neutralizing antibodies (NAB) using a pharmacodynamic study design. Thirty patients were enrolled. Blood samples were drawn at pre-treatment, 4-, 8-h time points following the intramuscular dose of IFN-beta-1a. Total RNA was obtained from peripheral blood cells, processed to cDNA and analyzed using quantitative real-time polymerase chain reaction. Pre-treatment serum samples were analyzed for anti-IFN-beta binding and neutralizing antibodies: 22 patients were NAB negative; equal numbers of the eight remaining patients were either NAB positive or had borderline NAB status. The results showed that early assessment (at 4 h after IFN-beta injection) of mRNAs for Stat-1, MxA, MxB and TRAIL was more sensitive than the later measurements. Furthermore, the NAB positive patients had strongly attenuated gene expression responses on all the mRNAs. Patients with borderline NAB had average responses that appear to be lower than NAB negative patients on several genes, notably Stat-1, TRAIL and beta2 microglobulin.

Adult↗

VizStruct for visualization of genome-wide SNP analyses.

MOTIVATION: The size, dimensionality and the limited range of the data values make visualization of single nucleotide polymorphism (SNP) datasets challenging. The purpose of this study is to evaluate the usefulness of 3D VizStruct, a novel multi-dimensional data visualization technique for analyzing patterns in SNP datasets. RESULTS: VizStruct is an interactive visualization technique that reduces multi-dimensional data to two dimensions using the complex-valued harmonics of the discrete Fourier transform (DFT). In the 3D VizStruct extension, the multi-dimensional SNP data vectors are reduced to three dimensions using a combination of the DFT and the Kullback-Leibler divergence. The performance of 3D VizStruct was challenged with several biologically relevant published datasets that included human Chromosome 21, the human lipoprotein lipase (LPL) gene locus and the multi-locus genotypes of coral populations. In every case, the 3D VizStruct mapping provided an intuitive visual description of the key characteristics of the underlying multi-dimensional genotype.

Animals↗

Application of SPLINDID, a semiparametric, model-based method for pharmacogenomic modeling of mRNA dynamics.

PURPOSE: This study was conducted to evaluate the applicability of SPLINDID, a semiparametric, model-based approach for obtaining transcription rates from the pharmacodynamics of mRNA expression. METHODS: A nonparametric exponential cubic spline function was used to obtain the transcription rate profile and the dynamics of mRNA expression was fitted using compartmental approaches. The transcription rate profile and mRNA degradation parameter was estimated using maximum likelihood method of ADAPT II software. RESULTS: Data sets containing noise for mRNA levels were simulated for four diverse pharmaceutically relevant conditions: receptor nonlinearity, a model in which the variant mRNAs differing in mRNA degradation constants were transcribed and for a minimal model of the cell cycle. SPLINDID was able to fit the data sets and accurately recapitulate the transcription rate profiles normalized to the mRNA degradation rate constants. The model was also challenged using experimental data containing time profiles of cell-cycle-regulated genes. CONCLUSIONS: The SPLINDID approach is flexible in capturing complicated/complex mRNA profiles that are encountered in many experimental data sets.

Algorithms↗

Interferon inhibitory activity in patients with multiple sclerosis.

BACKGROUND: Interferon inhibitory activity (IIA) is a logical candidate for explaining neutralizing antibody-negative partial responsiveness to interferon beta in multiple sclerosis (MS), but its role has not been evaluated. OBJECTIVE: To investigate the role of IIA and soluble interferon-alpha/beta receptor (sIFNR) in determining response of patients with MS to interferon beta therapy. DESIGN: Parallel-group, open-label study. SETTING: Baird Multiple Sclerosis Center, Buffalo, NY. Patients Blood was obtained before and 24 hours after injection of interferon beta-1a from 38 anti-interferon beta neutralizing antibody-negative patients with relapsing-remitting MS and 16 untreated healthy controls. On the basis of clinical parameters of response to interferon beta therapy, the patients were divided into stable or good-responder (n = 20) and active or partial-responder (n = 18) groups. MAIN OUTCOME MEASURES: Quantitative analyses of magnetic resonance imaging were obtained; the IIA and sIFNR levels were measured using bioassay and enzyme-linked immunosorbent assay, respectively. RESULTS: The IIA and sIFNR levels were elevated in MS patients compared with controls (P<.001). The IIA levels were higher in active or partial responders compared with stable or good responders (P<.001); the sIFNR levels were not different between groups. The Extended Disability Status Score and T2 lesion volumes were higher in the active or partial-responder group compared with the stable or good-responder group. Interferon beta-1a did not have short-term effects on the IIA and sIFNR levels. In univariate general linear model and stepwise regression analyses, IIA levels were associated with T2 lesion volume. CONCLUSION: The levels of IIA are associated with increased MS disease activity and with responsiveness to interferon beta therapy in anti-interferon beta neutralizing antibody-negative MS patients.

Adult↗

Study of mitoxantrone for the treatment of recurrent neuromyelitis optica (Devic disease).

BACKGROUND: Neuromyelitis optica is a severe demyelinating disease that selectively involves the optic nerves and the spinal cord but usually spares the brain. It is considered to have a B-cell-induced pathogenesis. Mitoxantrone hydrochloride, a synthetic anthracenedione approved for worsening relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis, has been shown to primarily suppress the humoral response. OBJECTIVE: To evaluate the benefit of mitoxantrone treatment in patients with relapsing neuromyelitis optica. DESIGN: Prospective 2-year study. SETTING: Academic multiple sclerosis center. PATIENTS: Five patients (3 women and 2 men) with an age range of 20 to 51 years and an Expanded Disability Status Scale score of 2.5 to 6.5 (mean +/- SD, 4.40 +/- 1.88). INTERVENTIONS: Monthly intravenous infusions of mitoxantrone hydrochloride, 12 mg/m2, for 6 months followed by 3 additional treatments every 3 months. MAIN OUTCOME MEASURES: Expanded Disability Status Scale score measured every 3 months and during relapses; findings on orbital, brain, and spinal cord magnetic resonance images performed at baseline and at 3, 6, 12, 18, and 24 months; and visual evoked potentials and results of ophthalmologic evaluations performed at baseline and annually. RESULTS: During the 2 years of treatment, 2 patients each had a relapse once within the initial 5 months of treatment (1 severe and 1 moderate). Improvement was seen clinically and on magnetic resonance images in 4 patients. Patients generally tolerated the treatment well, although 1 patient had a reversible decrease in cardiac ejection fraction. CONCLUSION: Our results suggest a beneficial effect of mitoxantrone treatment for relapsing neuromyelitis optica.

Adult↗

Interferon-beta modulates bone-associated cytokines and osteoclast precursor activity in multiple sclerosis patients.

PURPOSE: Multiple sclerosis (MS) patients have a high risk of low bone density. The purpose of this study was to examine the molecular mechanisms potentially capable of modulating bone homeostasis in response to interferon-beta-1a (IFN-beta-1a) treatment and the focus was the bone-modulating system comprised of receptor activator of nuclear factor-kappaB (RANK), its ligand RANKL and its decoy receptor, osteoprotegerin (OPG). METHODS: In this open-label pharmacodynamic study, peripheral blood was obtained from relapsing-remitting MS patients just prior to and at multiple time points after intramuscular injection of 30 microg IFN-beta-1a. Samples were analysed for RANKL, tumour necrosis factor related apoptosis-inducing ligand (TRAIL), OPG and macrophage inflammatory protein-1 alpha/beta expression. Osteoclast precursor differentiation from peripheral blood cells of MS patients in the presence of exogenously added IFN-beta-1a was also assessed. Additionally, the changes in plasma levels of osteocalcin and the C-telopeptides after 1 year of treatment were measured as surrogate markers of bone formation and degradation, respectively. RESULTS: IFN-beta-1a treatment modulated RANKL and OPG in a selective, time-dependent manner. The levels of OPG protein decreased 25% at the 8-h time point, then increased 43% at the 24-h time point. The levels of free RANKL reached a maximum at the 8-h time point. Increases in the levels of macrophage inflammatory protein-1beta (MIP-1beta), a chemokine that increases osteolysis, were observed. The levels of the bone formation marker, osteocalcin, were lower in MS patients compared to controls and increased after one year of treatment. Ex vivo treatment of peripheral blood lymphocytes with IFN-beta resulted in a marked reduction of osteoclast-like cells in the presence of RANKL and macrophage colony stimulating factor. CONCLUSIONS: IFN-beta treatment induces complex, specific and time-dependent changes in multiple proteins and mRNAs related to bone homeostasis in MS patients.

Adult↗

SPLINDID: a semi-parametric, model-based method for obtaining transcription rates and gene regulation parameters from genomic and proteomic expression profiles.

PURPOSE: To evaluate a semi-parametric, model-based approach for obtaining transcription rates from mRNA and protein expression. METHODS: The transcription profile input was modeled using an exponential function of a cubic spline and the dynamics of translation; mRNA and protein degradation were modeled using the Hargrove-Schmidt model. The transcription rate profile and the translation, and mRNA and protein degradation rate constants were estimated by the maximum likelihood method. RESULTS: Simulated datasets generated from the stochastic, transit compartment and dispersion signaling models were used to test the approach. The approach satisfactorily fit the mRNA and protein data, and accurately recapitulated the parameter and the normalized transcription rate profile values. The approach was successfully used to model published data on tyrosine aminotransferase pharmacodynamics. CONCLUSIONS: The semi-parametric approach is effective and could be useful for delineating the genomic effects of drugs. AVAILABILITY: Code suitable for use with the ADAPT software program is available from the corresponding author. CONTACT: murali@acsu.buffalo.edu.

Algorithms↗

Low fat dietary intervention with omega-3 fatty acid supplementation in multiple sclerosis patients.

OBJECTIVES: To determine whether a low fat diet supplemented with omega-3 positively affects quality of life (QOL) in relapsing-remitting MS (RRMS) patients. In this 1-year long double-blind, randomized trial, patients were randomized to two dietary interventions: the "Fish Oil" (FO) group received a low fat diet (15% fat) with omega-3 FOs and the "Olive Oil" (OO) group received the AHA Step I diet (fat 30%) with OO supplements. The primary outcome measure was the Physical Components Summary Scale (PCS) of the Short Health Status Questionnaire (SF-36). Additional measures using MS specific QOL questionnaires, neurological status and relapse rate were obtained. RESULTS: 31 RRMS patients were enrolled, with mean follow up over 11 +/- SD 2.9 months. Clinical benefits favoring the FO group were observed on PCS/SF-36 (P = 0.050) and MHI (P = 0.050) at 6 months. Reduced fatigue was seen on the OO diet at 6 months (P = 0.035). The relapse rate decreased in both groups relative to the rates during the 1 year preceding the study: mean change in relapse rate in the FO group: -0.79 +/- SD 1.12 relapses/year (P = 0.021) vs. -0.69 +/- SD 1.11 (P = 0.044) in the OO group. This study suggests that a low fat diet supplemented with omega-3 PUFA can have moderate benefits in RRMS patients on concurrent disease modifying therapies.

Adolescent↗

ESPD: a pattern detection model underlying gene expression profiles.

MOTIVATION: DNA arrays permit rapid, large-scale screening for patterns of gene expression and simultaneously yield the expression levels of thousands of genes for samples. The number of samples is usually limited, and such datasets are very sparse in high-dimensional gene space. Furthermore, most of the genes collected may not necessarily be of interest and uncertainty about which genes are relevant makes it difficult to construct an informative gene space. Unsupervised empirical sample pattern discovery and informative genes identification of such sparse high-dimensional datasets present interesting but challenging problems. RESULTS: A new model called empirical sample pattern detection (ESPD) is proposed to delineate pattern quality with informative genes. By integrating statistical metrics, data mining and machine learning techniques, this model dynamically measures and manipulates the relationship between samples and genes while conducting an iterative detection of informative space and the empirical pattern. The performance of the proposed method with various array datasets is illustrated.

Algorithms↗

VizStruct: exploratory visualization for gene expression profiling.

MOTIVATION: DNA arrays provide a broad snapshot of the state of the cell by measuring the expression levels of thousands of genes simultaneously. Visualization techniques can enable the exploration and detection of patterns and relationships in a complex data set by presenting the data in a graphical format in which the key characteristics become more apparent. The dimensionality and size of array data sets however present significant challenges to visualization. The purpose of this study is to present an interactive approach for visualizing variations in gene expression profiles and to assess its usefulness for classifying samples. RESULTS: The first Fourier harmonic projection was used to map multi-dimensional gene expression data to two dimensions in an implementation called VizStruct. The visualization method was tested using the differentially expressed genes identified in eight separate gene expression data sets. The samples were classified using the oblique decision tree (OC1) algorithm to provide a procedure for visualization-driven classification. The classifiers were evaluated by the holdout and the cross-validation techniques. The proposed method was found to achieve high accuracy. AVAILABILITY: Detailed mathematical derivation of all mapping properties as well as figures in color can be found as supplementary on the web page http://www.cse.buffalo.edu/DBGROUP/bioinformatics/supplementary/vizstruct. All programs were written in Java and Matlab and software code is available by request from the first author.

Algorithms↗

Analysis of pharmacokinetics, pharmacodynamics, and pharmacogenomics data sets using VizStruct, a novel multidimensional visualization technique.

PURPOSE: Data visualization techniques for the pharmaceutical sciences have not been extensively investigated. The purpose of this study was to evaluate the usefulness of VizStruct, a multidimensional visualization tool, for applications in pharmacokinetics, pharmacodynamics, and pharmacogenomics. METHODS: The VizStruct tool uses the first harmonic of the discrete Fourier transform to map multidimensional data to two dimensions for visualization. The mapping was used to visualize several published pharmacokinetic, pharmacodynamic, and pharmacogenomic data sets. The VizStruct approach was evaluated using simulated population pharmacokinetics data sets, the data from Dalen and colleagues (Clin. PharmacoL Ther. 63:444-452, 1998) on the kinetics of nortriptyline and its 10-hydroxynortriptyline metabolite in subjects with differing number of copies of the CYP2D6, and the gene expression profiling data of Bohen and colleagues (Proc. Natl. Acad. Sci. USA 100:1926-1930, 2003) on follicular lymphoma patients responsive and nonresponsive to rituximab. RESULTS: The VizStruct mapping preserves the key characteristics of multidimensional data in two dimensions in a manner that facilitates visualization. The mapping is computationally efficient and can be used for cluster detection and class prediction in pharmaceutical data sets. The VizStruct visualization succinctly summarized the salient similarities and differences in the nortriptyline and 10-hydroxynortriptyline pharmacokinetic profiles in subjects with increasing number of CYP2D6 gene copies. In the simulated population pharmacokinetic data sets, it was capable of discriminating the subtle differences between pharmacokinetic profiles derived from 1- and 2-compartment models with the same area under the curve. The two-dimensional VizStruct mapping computed from a subset of 102 informative genes from the Bohen and colleagues data set effectively separated the rituximab responder, rituximab nonresponder, and control subject groups. CONCLUSIONS: The VizStruct approach is a computationally efficient and effective approach for visualizing complex, multidimensional data sets. It could have many useful applications in the pharmaceutical sciences.

Algorithms↗

Risk of bone loss in men with multiple sclerosis.

CONTEXT: Osteoporosis and the increased fracture risk associated with osteoporosis become apparent in men approximately 10 years later than women. However, in recent studies, approximately 20% of healthy men in the age range 55-64 years were found to be osteopenic. Emerging data suggest a significantly increased prevalence of osteoporosis in men and women with multiple sclerosis (MS) compared to age-matched controls, but no specific clinical testing recommendations are available for men. OBJECTIVE: To determine the proportion of male MS patients with osteoporosis and to identify the factors associated with the reduction in bone mass. DESIGN: Consecutive male MS patients seen at our MS clinic were screened with dual-X-ray absorptiometry (DEXA) scan for determining the bone mineral density (BMD). All patients had neurological Expanded Disability Status Scale (EDSS) evaluation. The results were compared to healthy age-matched male reference population using the Z score and to a cohort of women MS patients and women controls. Calcium, total testosterone, sex-hormone binding globulin (SHBG), 25-hydroxy-vitamin-D, and parathyroid hormone (PTH) were evaluated in male patients with decreased BMD. Relevant data on body mass index (BMI), medication, alcohol consumption, smoking, and sexual dysfunction were recorded. SETTING: Academic MS Centre. PATIENTS AND OTHER PARTICIPANTS: Forty consecutive male MS patients, age mean 51.2 +/- 8.7 years, and mean EDSS of 5.8 +/- 1.9 were evaluated with DEXA scan. Of these, 17.5% patients were relapsing-remitting (RR) MS, 57.5% were secondary progressive (SP) MS and 25% were primary progressive (PP) MS. MAIN OUTCOME MEASURE: Proportion of male MS patients with reduced BMD at the lumbar spine and femoral neck. RESULTS: Thirty-two (80%) of our patients had a reduced bone mass of either lumbar spine or the femoral neck; of these 17 patients (42.5%) had osteopenia and 15 patients (37.5%) had osteoporosis. Twenty-one per cent (eight out of 38 patients) had vertebral, rib or extremities fractures. Multivariate linear regression analysis indicated that the EDSS (P < 0.0001) and BMI (P = 0.0004) were the important factors associated with low BMD at the femoral neck and the EDSS was the important factor (P = 0.0017) associated with low BMD at the lumbar spine. The same factors emerged as significantly associated with the corresponding Z scores, which are corrected for age and sex. No clear association between intravenous steroid therapy and BMD was evident in the multivariate analysis. Low levels of 25-hydroxy-vitamin-D were seen in 37.5% of patients. CONCLUSIONS: The proportion of male MS patients with reduced bone mass is high and disproportionate to their age and ambulation, consistent with an association between the MS disease process and pathological bone loss. Increased awareness and bone density screening of male and female MS patients over 40 years of age is warranted.

Absorptiometry, Photon↗

Genomic effects of IFN-beta in multiple sclerosis patients.

The purpose of this report was to characterize the dynamics of the gene expression cascades induced by an IFN-beta-1a treatment regimen in multiple sclerosis patients and to examine the molecular mechanisms potentially capable of causing heterogeneity in response to therapy. In this open-label pharmacodynamic study design, peripheral blood was obtained from eight relapsing-remitting multiple sclerosis patients just before and at 1, 2, 4, 8, 24, 48, 120, and 168 h after i.m. injection of 30 micro g of IFN-beta-1a. The total RNA was isolated from monocyte-depleted PBL and analyzed using cDNA microarrays containing probes for >4000 known genes. IFN-beta-1a treatment resulted in selective, time-dependent effects on multiple genes. The mRNAs for genes implicated in the anti-viral response, e.g., double-stranded RNA-dependent protein kinase, myxovirus resistance proteins 1 and 2, and guanylate binding proteins 1 and 2 were rapidly induced within 1-4 h of IFN-beta treatment. The mRNAs for several genes involved in IFN-beta signaling, such as IFN-alpha/beta receptor-2 and Stat1, were also increased. The mRNAs for lymphocyte activation markers, such as IFN-induced transmembrane protein 1 (9-27), IFN-induced transmembrane protein 2 (1-8D), beta(2)-microglobulin, and CD69, were also increased in a time-dependent manner. The findings demonstrate that IFN-beta treatment induces specific and time-dependent changes in multiple mRNAs in lymphocytes of multiple sclerosis patients that could provide a framework for rapid monitoring of the response to therapy.

Adult↗

Sex differences in in vitro pro-inflammatory cytokine production from peripheral blood of multiple sclerosis patients.

We compared the patterns of the pro-inflammatory cytokines, interferon-gamma (IFN-gamma), interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-alpha), and the anti-inflammatory cytokines, interleukin-10 (IL-10) and tumor growth factor-beta (TGF-beta) from peripheral blood of male and female patients with relapsing-remitting (RR) and secondary progressive (SP) forms of multiple sclerosis (MS). The relationships between pro-inflammatory cytokines and disability (expanded disability status scale, EDSS) were also examined. Peripheral blood anti-coagulated with heparin was obtained from 47 MS patients (30 women and 17 men) and activated with phorbol-12-myristate 13 acetate (PMA) and ionomycin in the presence of brefeldin A and stained for flow cytometry with fluorescently labeled antibodies against intracellular IFN-gamma, TNF-alpha, IL-2, IL-4 and IL-10. The T cells were delineated with peridinin chlorophyll protein (Per-CP) labeled anti-CD3 antibody. The stained samples were analyzed on a flow cytometer to assess the intracellular pro-inflammatory cytokine patterns. The levels of interleukin-10 (IL-10) and tumor growth factor-beta (TGF-beta) were measured in plasma using enzyme-linked immunoassay. The percentage of TNF-alpha-producing CD3 positive cells was significantly higher (P=0.045) in men (mean+/-S.D., 39+/-13%) than in women (mean+/-S.D., 29+/-13%) RR-MS patients. The percentage of CD3 positive cells producing IFN-gamma was significantly correlated with EDSS in females but not in males (Spearman rank correlation r(S)=0.49, P=0.018). The secretion of the pro-inflammatory cytokines, IFN-gamma and TNF-alpha, is influenced by gender in MS patients and may contribute to the sexual dimorphism of MS.

Adolescent↗