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PubMed2004

Finite width model sequence comparison.

Sequence comparison is a widely used computational technique in modern molecular biology. In spite of the frequent use of sequence comparisons, the important problem of assigning statistical significance to a given degree of similarity is still outstanding. Analytical approaches to filling this gap usually make use of an approximation that neglects certain correlations in the disorder underlying the sequence comparison algorithm. Here, we use the longest common subsequence problem, a prototype sequence comparison problem, to analytically establish that this approximation does make a difference to certain sequence comparison statistics. In the course of establishing this difference we develop a method that can systematically deal with these disorder correlations.

Algorithms↗

PubMed2001

Combination of matrix solid-phase dispersion extraction and direct on-line liquid chromatography-nuclear magnetic resonance spectroscopy-tandem mass spectrometry as a new efficient approach for the rapid screening of natural products: application to the total asterosaponin fraction of the starfish Asterias rubens.

A combination of matrix solid-phase dispersion extraction (MSPD) and LC-NMR-MS hyphenation is proposed as a rapid screening method of natural products for unknown compounds. In this report, this new analytical approach is applied for the first time. MSPD represents a significant simplification compared to classical extraction procedures and is thus an excellent complement to the fast and powerful LC-NMR-MS: MSPD yields extracts suitable for LC-NMR-MS in one simple preparation step, while LC-NMR-MS yields a wealth of information in one single chromatographic run. The suitability of this technique to characterise glycosidic compounds in the molecular mass range of 1200 to 1400 a.m.u. is demonstrated. The information on the number of exchangeable protons provided by an additional back-exchange experiment proved to be particularly valuable for structural elucidation. The possibility of semi-quantitative LC-NMR measurements through methyl signals H(3)-18 and 19 of the steroidal skeleton is demonstrated and is ensuingly used to provide relative quantitative data of the steroid oligosaccharide fraction.

Animals↗

PubMed1995

Methodological and statistical approaches to criteria development in rheumatic diseases.

We have discussed methodological and statistical considerations in developing disease classification and assessment criteria. In choosing cases with disease and nondisease controls, classification criteria should be developed with an eye toward face, content and construct validity, and toward their ultimate applicability. The validity of disease criteria should be tested in a patient sample different from the one used to develop the criteria. Several analytic approaches are available to reduce the candidate diagnostic elements to those that will define the presence of disease. Methodological issues in the assessment of disease severity, activity or damage are similar to those faced in criteria development studies, although the analytic concerns are different and the options more varied.

Humans↗

PubMed1991

An approach to several problems in using large databases for population-based case-control studies of the therapeutic efficacy and safety of anti-hypertensive medicines.

In this paper we discuss approaches to two distinct problems in using large computerized databases to conduct population-based case-control studies. The first topic, concerning case ascertainment, is a methodologic problem, and the second, concerning confounding by indication, is an analytic problem. The first involves attempting to ascertain all incident cases of coronary disease among enrollees of Group Health Cooperative of Puget Sound (GHC), a large health-maintenance organization. Methodologic studies reported here have helped us improve the efficiency of using the large computerized databases for case ascertainment at GHC. The second problem involves the issue of confounding by drug indication. Drugs such as beta-blockers have multiple indications, including the treatment of both high blood pressure and angina. These two indications may make it difficult in an observational study to determine whether beta-blockers may prevent coronary disease in patients with high blood pressure. We discuss here our current thinking about the best analytic approach to this problem.

Adrenergic beta-Antagonists↗

PubMed2006

A generalized analysis of capillary flows in channels.

Investigations on the motion of a fluid in capillary geometries have been extensively reported in the literature using both experimental and theoretical approaches. In this paper, the theories for capillary flow are generalized to a unified nonlinear second-order differential equation which takes the effects of the entrance, the inertial forces, and the dynamic contact angle into account. An analytical solution of the differential equation is obtained in the form of a double Dirichlet series. The readily evaluated analytical solution is compared with experimental and numerical results in the literature, which shows a good agreement. It is demonstrated that this analytical approach can be used to predict capillary flows for a wide range of fluids and parallel-plate and tube geometries in a unified manner.

Journal Article↗

PubMed1991

Epidemiologic approaches for assessing health risks from complex mixtures in indoor air.

Indoor air may be contaminated by diverse gaseous and particulate pollutants that may adversely affect health. As a basis for controlling adverse health effects of indoor air pollution, the presence of a hazard needs to be confirmed, and the quantitative relationship between exposure and response needs to be described. Toxicological, clinical, and epidemiological studies represent complementary approaches for obtaining the requisite evidence. The assessment of the effects of complex mixtures poses a difficult challenge for epidemiologists. Understanding the effects of exposure may require accurate assessment of concentrations and personal exposures to multiple agents and analytical approaches that can identify independent effects of single agents and the synergistic or antagonistic effects that may occur in mixtures. The array of epidemiological study designs for this task includes descriptive studies, cohort studies, and case-control studies, each having potential advantages and disadvantages for studying complex mixtures. This presentation considers issues related to exposure assessment and study design for addressing the effects of complex mixtures in indoor air.

Air Pollution, Indoor↗

PubMed2004

A cell fractionation approach for the quantitative analysis of subcellular drug disposition.

PURPOSE: The purpose of this work was to develop and validate a method that can be used to quantify drugs associated with intracellular compartments. METHODS: The human leukemic cell line U-937 was used to evaluate the distribution of model compounds with known and different subcellular distribution profiles. Lysotracker Red is a lysosomal vital stain and doxorubicin is an anticancer agent with a strong propensity for nuclear accumulation in U-937 cells. After incubation with compounds, cells were separated into fractions containing nuclei, cytosol, and cytoplasmic organelles (lysosomes, mitochondria, Golgi apparatus). Compounds contained within isolated fractions were subsequently extracted and analyzed by high-performance liquid chromatography. Diffusion of compounds from isolated organelles was also investigated. RESULTS: Using this approach we have shown that the model compounds Lysotracker Red and doxorubicin preferentially accumulated within lysosomes and nuclei, respectively. We have reproducibly determined concentrations of these compounds in each of the cellular fractions. We have also shown that diffusion of these compounds from isolated cellular compartments was minimal during the time required to complete the experimental procedure. CONCLUSIONS: The analytical approach described in this manuscript yielded reproducible quantitative data regarding the intracellular distribution of model compounds in U-937 cells. With the aid of a relatively sensitive analytical assay, this technique should be useful for most drugs that have a specific concentrative mechanism for organelle accumulation similar to Dox and LTR.

Cell Fractionation↗

PubMed2003

Systematic reviews with individual patient data meta-analysis to evaluate diagnostic tests.

Systematic literature reviews with meta-analysis of reported data in diagnostic research studies about the accuracy of tests assist clinicians in decision-making. However, there are limitations to this approach as the analysis of such data often does not allow reviewers to explore the diagnostic information gained from combinations of tests. In recent years meta-analysis of individual patient data (IPD) has been introduced as gold standard analytic approach in systematic reviews of randomised controlled trials. Application of IPD meta-analysis in systematic reviews of diagnostic tests can allow advanced analysis to decipher the real value of testing. In particular, the additional information provided by testing can be examined in light of the information already known from history and examination. To our knowledge there are no IPD meta-analyses in diagnostic research so far. This commentary aims to highlight the benefits of IPD meta-analysis in the diagnostic domain and demonstrates how strategies for diagnostic work-up of women with postmenopausal bleeding could be improved using this approach in systematic reviews of diagnostic research on accuracy of ultrasound and hysteroscopy.

Diagnostic Tests, Routine↗

PubMed2003

Detection of selenocompounds in a tryptic digest of yeast selenoprotein by MALDI time-of-flight MS prior to their structural analysis by electrospray ionization triple quadrupole MS.

MALDI-TOFMS was proposed as a key technique to a novel generic approach for the speciation analysis of selenium in yeast supplements. Owing to a lower detection limit and superior matrix tolerance to electrospray MS it allowed a successful detection of selenocompounds in samples for which electrospray MS had failed. The analytical approach developed was applied to the identification of a previously unreported selenopentapeptide (m/z 596) in the tryptic digest of a water-soluble selenoprotein fraction isolated by size-exclusion chromatography. The information on the mass of the protonated molecular ion obtained from MALDI allowed the optimization of the conditions for collision induced dissociation MS using a triple quadrupole spectrometer that enabled the determination of the amino acid sequence SeMet-Asn-Ala-Gly-Arg of the selenopeptide.

Dietary Supplements↗

PubMed1998

The glycosylation heterogeneity of recombinant human IFN-gamma.

The cloning of the cDNA for human interferon-gamma (IFN-gamma) has resulted in its expression in Escherichia coli, baculovirus-infected insect cells, Chinese hamster ovary (CHO) cells, and the mammary gland of transgenic mice. Large quantities of highly purified recombinant IFN-gamma have been generated, aided by the use of highly specific neutralizing monoclonal antibodies, with a view to its production as a human therapeutic protein. The primary source of structural heterogeneity for IFN-gamma during its production in mammalian expression systems is glycosylation, which can profoundly affect the three-dimensional structure of a glycoprotein and its biological function. A number of analytical approaches have been developed recently to allow a detailed analysis of the carbohydrate structures associated with IFN-gamma, the principal advances being in the areas of capillary electrophoresis and mass spectrometry. The implementation of these high-resolution analytical tools to determine the glycosylation profile of IFN-gamma makes it one of the best characterized recombinant glycoproteins. Recombinant human IFN-gamma acts as a model secretory glycoprotein, typifying the intrinsic glycosylation processing events associated with production of a potential therapeutic glycoprotein.

Animals↗

PubMed2006

Antibody microarray-based oncoproteomics.

The driving force behind oncoproteomics is the belief that certain protein signatures or patterns exist that are associated with a particular malignancy. If so, the correlation of clinical parameters with defined protein expression patterns would allow us to predict disease progression and perhaps even postulate improved therapeutic modalities. The technological challenges to achieve these goals are significant, as the human proteome is not defined. No general methodological approach exists today, and human cancer can, furthermore, be divided into several disease subgroups. One potential solution to finding cancer-associated protein signatures is the emerging technology of affinity proteomics. This approach addresses some of the shortcomings of traditional proteomics and combines it with the power of microarrays. The present review focuses on the role of antibody microarrays in oncoproteomics and its potential to provide a truly proteome-wide analytical approach.

Antibodies↗

PubMed1999

Sibling aggregation for psychopathology in offspring of opiate addicts: effects of parental comorbidity.

Applied a new analytic approach within the high-risk paradigm, the analysis of sibling aggregation, to identify homogeneous subtypes of familial risk for psychopathology and addiction. All sibling pairs participating in a study of offspring of opiate-addicted parents were identified and their aggregation for psychiatric disorders was determined using pairwise odds ratios, an analytic technique used in genetic epidemiology. Sibling aggregation was most notable for depressive and anxiety disorders but only in the presence of comorbid depressive disorders in the parents. Parental comorbid alcoholism did not impact sibling aggregation. We emphasize methodological implications of this approach for addressing issues of phenotypic and etiologic heterogeneity in the study of developmental risk for substance abuse.

Adolescent↗

PubMed2002

Molecular identification of organic compounds in atmospheric complex mixtures and relationship to atmospheric chemistry and sources.

This article describes a chemical characterization approach for complex organic compound mixtures associated with fine atmospheric particles of diameters less than 2.5 m (PM2.5). It relates molecular- and bulk-level chemical characteristics of the complex mixture to atmospheric chemistry and to emission sources. Overall, the analytical approach describes the organic complex mixtures in terms of a chemical mass balance (CMB). Here, the complex mixture is related to a bulk elemental measurement (total carbon) and is broken down systematically into functional groups and molecular compositions. The CMB and molecular-level information can be used to understand the sources of the atmospheric fine particles through conversion of chromatographic data and by incorporation into receptor-based CMB models. Once described and quantified within a mass balance framework, the chemical profiles for aerosol organic matter can be applied to existing air quality issues. Examples include understanding health effects of PM2.5 and defining and controlling key sources of anthropogenic fine particles. Overall, the organic aerosol compositional data provide chemical information needed for effective PM2.5 management.

Aerosols↗

PubMed2006

FDA perspective on trials with interim efficacy evaluations.

Over the years FDA has seen a variety of 'adaptive' approaches, including repeated calculation of p-values. More recently there has been interest in adjusting sample sizes based on event rates, easy if the treatment group rates remain blinded but possible even with unblinded analysis. In large trials, group sequential analytic approaches are routine. Early stopping however, can reduce available data and in cardiac trials we have generally urged use of only survival as the basis for stopping, even if the primary endpoint is a composite (death, new AMI, etc). Other possibilities include adaptive randomization and starting additional dose groups. Enrichment designs focus on populations with a higher event rate or on populations more likely to respond. They can reduce sample sizes and target therapy toward people most likely to benefit.

Clinical Trials as Topic↗

PubMed2025

Circulating inflammatory proteins and osteomyelitis: A bidirectional Mendelian randomization and colocalization analysis.

Circulating inflammatory proteins (CIPs) have been implicated in the progression of osteomyelitis (OM); however, whether these proteins play a causal role or are merely a consequence remains unclear. This study aimed to assess the causal relationships between CIPs and OM using a bidirectional 2-sample Mendelian randomization (MR) approach. MR analyses were performed using genome-wide association study summary statistics for 91 inflammation-related proteins (n = 14,824) and OM (1881 cases and 3,91,037 controls). The inverse variance weighted method was used as the primary analytical approach, supplemented by MR-Egger, weighted median, simple mode, and weighted mode methods. Sensitivity analyses were conducted to evaluate heterogeneity, horizontal pleiotropy, and robustness. Colocalization analysis was applied to identify shared causal variants, and pathway enrichment analysis was used to explore underlying biological mechanisms. Forward MR analysis revealed that elevated levels of tumor necrosis factor-beta (TNF-β) were significantly associated with increased OM risk (odds ratio [OR] = 1.132; 95% confidence interval [CI]: 1.052-1.217; false discovery rate [FDR] = 0.027). Conversely, decreased levels of osteoprotegerin (OR = 0.772; 95% CI: 0.671-0.889; FDR = 0.015) and adenosine deaminase (OR = 0.811; 95% CI: 0.736-0.894; FDR < 0.001) were associated with increased OM risk. Reverse MR analysis identified increased levels of interleukin-15 receptor alpha, C-X-C motif chemokine ligand 1, fms-related tyrosine kinase 3 ligand, interleukin-20, interleukin-10 (IL10), C-C motif chemokine ligand 19, and CXCL6 as being significantly associated with OM susceptibility (all FDR < 0.05). Colocalization analysis provided strong evidence for a shared causal variant between TNF-β and OM (posterior probability for hypothesis 4 = 0.999). Enrichment analyses indicated involvement of implicated proteins in Toll-like receptor signaling and T-helper 17 cell differentiation pathways. This study identified several CIPs - including TNF-β, osteoprotegerin, and adenosine deaminase - as potentially causal in OM development. These findings highlight promising targets for future immunomodulatory therapies aimed at preventing or mitigating osteomyelitis.

Humans↗

PubMed2006

Modeling exposures for DNA methylation profiles.

We extend the finite mixture model to estimate the association between exposure and latent disease subtype measured by DNA methylation profiles. Estimates from this model are compared with those obtained from the simpler two-phase approach of first clustering the DNA methylation data followed by associating exposure with disease subtype using logistic regression. The two models are fit to data from a study of colorectal adenomas and are compared in a simulation study. Depending on the analytic approach, we obtain different estimates of the odds ratio (OR) and its 95% confidence interval (95% CI) for the association of RBC folate and DNA methylation subtype in colorectal adenomas (OR, 0.31; 95% CI, 0.08-1.26 from the extended finite mixture model; OR, 0.44; 95% CI, 0.15-1.28 from the two-phase approach; n = 58 case subjects). Although our results could be a chance occurrence due to fluctuations from small sample size, we did a simulation study using larger samples and found that differences between the two approaches emerge when there is noise in the cluster analysis. In the naive two-phase approach, the estimate of the OR is biased towards the null, and its SE is underestimated when there is error in the cluster assignment. Estimates from the extended mixture model are unbiased and have the correct SE estimate but may require larger sample sizes for convergence. Thus, when the clusters are not identified with certainty, the extended mixture model is preferred for valid estimation of the OR and CI.

Adenoma↗

PubMed2004

A stochastic approach for the apodization of very short arrays.

The problem addressed in this paper is the synthesis of the weight coefficients to be assigned to the elements of a linear array that has a spatial aperture shorter than one wavelength. The aim is to obtain a data-independent beam pattern that fulfills some a priori fixed constraints. The analytical approach, expressed in terms of a linear least-squares problem, has been attempted, resulting in very large noise sensitivity and beam pattern instability. To overcome this problem a mixed methodology, based on a combination of a stochastic technique and a local descent method that provides very robust weight coefficients with reduced noise sensitivity, is proposed. Here, robust means that, even if unavoidable fluctuations occur in the transducer gains, the beam pattern obtained maintains the desired features.

Journal Article↗

PubMed2001

The Pavia approach to clinical protein analysis.

The protein chemistry laboratory of the Pavia University Hospital is specialized in the study of monoclonal components in body fluids. It is closely connected with the research laboratory devoted to the structural and functional study of pathogenic proteins and with the Clinical Chemistry Central Laboratory. The analyses are performed on specific medical request. The analytical approach is mainly based on analysis of patient's serum and urine by high-resolution agarose gel electrophoresis and immunofixation with the possible addition of the quantification of specific proteins. The interpretation of the protein pattern and the final reporting result from the integration of the laboratory data with the clinical information. This labor-intensive approach requires skills in the performance of protein analysis and in the interpretation/referral phase, as well as close communication with the attending physician.

Clinical Chemistry Tests↗